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  • Digitale Medien  (198)
  • 2000-2004  (198)
  • 1890-1899
  • 1830-1839
  • apoptosis  (117)
  • chemotherapy  (81)
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  • Digitale Medien  (198)
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  • 1
    ISSN: 1432-2013
    Schlagwort(e): Key words vitamin C (L-ascorbic acid) ; apoptosis ; human articular chondrocytes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Chondrocytes present in articular cartilage survive as a resident cell population throughout the lifespan of the individual organism. However, articular chondrocytes as other cells also undergo apoptosis and there is an ever increasing list of diverse stimuli that can induce this phenomenon in vitro. Our main interest was to investigate potential cytotoxic effects of vitamin C (L-ascorbic acid) on human articular chondrocytes. The present study suggests that vitamin C can induce apoptosis in a cell culture of chondrocytes after 18 h of cultivation. Apoptosis-inducing activity of L-ascorbic acid is dose dependent and significantly affected by the presence of serum. The increased number of vitamin C induced apoptotic cells was associated with DNA fragmentation and morphological changes of the cells.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1569-8041
    Schlagwort(e): BEACOPP ; chemotherapy ; dose intensification ; hematotoxicity ; Hodgkin's disease ; practicability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Evidence is recently accumulating that the novelBEACOPP (bleomycin (B), etoposide (E), adriamycin (A), cyclophosphamide (C),vincristine (O), procarbazine (P), prednisone (P)) chemotherapy is a highlyeffective treatment for advanced stage Hodgkin's disease. Two dose variantsof BEACOPP are currently tested in a phase III randomized multicenter trialof the GHSG. To enable more extensive testing of BEACOPP we characterized itspracticability regarding schedule adherence, acute hematotoxicity and need forsupportive treatment. Patients and methods:Data of 858 patients (6592 therapy cycles)from 184 participating institutions were evaluated. Planned total drug dosesof the baseline variant (arm 1) were 80, 2400, 200, 5200, 11.2, 5600 and 4480mg/m2 for B, E, A, C, O, P and P, respectively. Compared to arm 1,the doses of E, A and C in the dose-intensified variant (arm 2) were escalatedby factor 2.0, 1.4, 1.92, respectively, using G-CSF assistance. Stepwise dosereductions were specified in case of dose-limiting toxicities. Both variantsare given in eight three-weekly courses. Results:Median dose adherence (dose actually given relative toplanned arm 1 dose) in arm 1 was 1.0 for all drugs. Relative dose escalationof E, A, and C actually maintained in arm 2 was 1.83, 1.37 and 1.77 (medians),respectively, and 70% of patients maintained elevated dose levelsthroughout the entire treatment. Dose-limiting toxicities occurred in25% of cycles in arm 2, most frequently due to leukocytopenia andthrombocytopenia. Time courses of leukocytes in arm 2 showed more severe butnot more prolonged leukocytopenia compared with arm 1. WHO grades 3–4infections were documented in 2.1% (arm 1) and 3.1% (arm 2) ofall cycles. Erythrocytes were transfused in 6% (arm 1) and 28%(arm 2), platelets in 〈1% (arm 1) and 6% (arm 2) of allcycles. Conclusions:Both BEACOPP schemes are practicable in a largemulticenter setting. Despite increased hematotoxicity, moderate doseescalation is safe for the majority of the patients with G-CSF assistance andstandard supportive treatment.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; 5-FU ; folinic acid ; gemcitabine ; Gemzar® ; pancreas cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Gemcitabine (Gemzar®) and 5-fluorouracil (5-FU)plus folinic acid (FA) both have proven activity in the treatment of patientswith advanced pancreatic cancer. The present study was initiated toinvestigate the efficacy of gemcitabine in combination with 5-FU–FA. Patients and methods:Thirty-eight patients, median age 60 years(range 34–70) with inoperable, stage IV, pancreatic cancer were enrolledinto the study and treated on an outpatient basis. All except one patientreceived at least one cycle of treatment with gemcitabine (1000mg/m2), followed by FA (200 mg/m2) and 5-FU (750mg/m2) administered as a 24-hour continuous infusion on days 1, 8,15 and 22 of a 42-day schedule. No patient had received prior chemotherapy orradiotherapy. All 38 patients were assessed for efficacy, toxicity and timeto progressive disease. Results:Two patients (5%), achieved a partial response andthirty-four patients (89%) achieved stable disease. There were twoearly deaths (≤4 weeks). The median time to progression was 7.1 months(range 0.4–18.1+; 95% confidence interval (95% CI):5.3–7.9 months). Three patients had a progression-free interval ofgreater than 12 months and 12 of 38 patients (32%) survived longer than12 months. The median overall survival was 9.3 months (range 0.5–26.5;95% CI: 7.3–13.0 months). The incidence of grade 3 and 4toxicities was low. Conclusions:The combination of gemcitabine and 5-FU–FA isactive and well tolerated and seems to offer an improvement inprogression-free interval over both gemcitabine monotherapy and 5-FU–FAtherapy.
    Materialart: Digitale Medien
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  • 4
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 217-220 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; Guillain–Barré syndrome ; lymphoma ; polyneuropathy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We describe a case of Guillain–Barré syndrome (GBS) in apatient with non-Hodgkin's lymphoma (NHL). A 21-year-old woman with a newlydiagnosed stage IV high-grade lymphoma (precursor T-cell NHL according to theR.E.A.L. Classification) developed flaccid quadriparesis and bilateral facialdiplegia after three weeks of treatment with vincristine, daunorubicin,L-asparaginase and prednisolone. The clinical course and neurologicalexamination were consistent with GBS. Despite treatment with intravenousimmunoglobulins her neurological symptoms progressed. Plasmapheresis wastherefore initiated followed by intravenous immunoglobulins. After partialremission of neurologic symptoms, induction chemotherapy with cyclophosphamideand cytarabine was continued without any further complication. Three monthslater, the lymphoma was in complete remission. GBS has been described inHodgkin's disease and after bone marrow transplantation but is rare in NHL.In patients with NHL who develop neurological symptoms, drug toxicity andnervous system infiltration are the leading cause of neuropathology, but GBSshould be considered in the differential diagnosis.
    Materialart: Digitale Medien
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  • 5
    ISSN: 1569-8041
    Schlagwort(e): brain tumor ; chemotherapy ; encephalopathy ; late neurological toxicity ; leucoencephalopathy ; primary cerebral lymphoma ; radiochemotherapy ; systematic follow-up
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Primary cerebral non-Hodgkin's lymphomas (NHL) inimmunocompetent patients (PCL) are located exclusively in the central nervoussystem, the eye, or meninges. Clinical management of these patients remainscontroversial. Patients and methods:Clinical characteristics of the patients andparameters influencing their outcome as of December 1998 were investigated andregistered in a database of 226 patients treated in the French Federation ofCancer Centers between 1980 and 1995. Results:Most PCL are diffuse large-cell NHL with a B phenotype.The incidence of PCL has been steadily increasing over the past 20 years insome but not all countries. The overall survival of primary cerebral lymphoma(PCL) patients in the published series, a median of 12–16 months and afive-year survival of 5%–20%, is poor. Several series havenow reported long-term survivals of more than 10 years and PCL may thereforebe a curable tumor in some patients. The optimal treatment of PCL is notknown. Complete resection of the tumor does not improve outcome andmultidisciplinary approaches combining chemotherapy and radiotherapy are nowcommonly used, although the superiority of combination over radiotherapy- orchemotherapy-alone has never been demonstrated in a phase III trial. Theoptimal chemotherapy regimen, the dose and even the usefulness of brainradiotherapy after chemotherapy are therefore still matters of debate.Recently, several authors have reported a relatively high incidence of lateneurological sequelae after PCL treatment. Conclusions:The optimal treatment of PCL patients remains to bedefined. Large cooperative international phase III trials are now required todefine and improve the optimal treatment of PCL and reduce its sequelae.
    Materialart: Digitale Medien
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  • 6
    ISSN: 1569-8041
    Schlagwort(e): Charcot–Marie–Tooth disease ; chemotherapy ; hereditary motor and sensory neuropathy ; PMP22 ; vincristine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Severe up to life-threatening neuropathy has beenobserved in patients with hereditary neuropathies receiving vincristine. Case report:A 52-year-old female painter suffering fromhigh-grade non-Hodgkin's lymphoma (stage IVB) was treated with a total of 4mg of vincristine during two courses of CHOP chemotherapy (cyclophosphamide,vincristine, adriamycin, prednisone). At onset of treatment no neurologicalproblems were reported. There was good lymphoma response to chemotherapy. Atthe same time, however, the patient gradually developed dysphagia, dysarthria,muscular weakness of both lower and upper extremities, areflexia, paraesthesiaof the fingertips and bilateral sensory impairment of feet and lower legs.These symptoms continually worsened over a period of seven weeks until she wasunable to walk or to perform her work. Electrophysiological studies showedperipheral axonal and demyelinative sensorimotor neuropathy in correlation tohistological findings. Molecular analysis revealed 17p11.2 duplication typicalfor Charcot–Marie–Tooth disease IA. While continuing chemotherapywithout the use of vincristine the patient's neurologic symptoms slowlyrecovered within six months. Conclusion:Prior to administration of vincristine family andpatient history as well as physical examination should be performed carefullyto look for underlying hereditary neuropathy. For those patients with aclinical history or symptoms suggestive for CMT nerve conduction velocitystudies and on an individual base even molecular genetic analysis areneccessary to prevent serious neurologic complications.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1569-8041
    Schlagwort(e): carboplatin ; chemotherapy ; gemcitabine ; non-small-cell lung cancer ; paclitaxel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:The combination of paclitaxel (P) and carboplatin (C)is an effective treatment for advanced NSCLC. Gemcitabine (G) is an active newdrug. We planned a phase I study to find the maximum tolerated dose (MTD) ofthe PCG combination. A phase II study was subsequently conducted to evaluatethe activity and toxicity of PCG. Patients and methods:Forty-five patients entered the study.Twenty-eight had stage IIIA–B disease, 17 stage IV. In the phase Istudy, with a fixed dose of C at AUC = 6 on day 1, P was escalated usingincrements of 25 mg/m2 starting from 175 mg/m2 on day1 and G with increments of 200 mg/m2 starting from 800mg/m2 on day 1 and 8. Results:Fourteen patients entered the phase I study. The MTD wasreached at P 200 mg/m2, C AUC = 6 and G 1000 mg/m2.Neutropenic fever and grade 3 diarrhea were the dose limiting toxicities.Thirty-one patients were treated in the phase II study with P 175mg/m2, C AUC = 6 and G 1000 mg/m2. Response rate was57% (68% in stage III and 47% in stage IV).Myelosuppression was the main toxicity, with grade 3–4 leukopeniaoccurring in 35% of cases. Grade 3 anemia was observed in 24%of cases and grade 3–4 thrombocytopenia occurred in 34% ofpatients. Non-hematological toxicity was mild. Median survival and one-yearactuarial survival were 20.5 months and 74% for stage III and 11.5months and 47% for stage IV. Conclusions:PCG is a promising regimen for treating advancedNSCLC. A phase III study comparing PCG to paclitaxel plus carboplatin inadvanced NSCLC is ongoing. On the other hand, we are planning to introduce thePCG regimen in the treatment of stage II–III patients in the setting ofa multimodality treatment.
    Materialart: Digitale Medien
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  • 8
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 1615-1616 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gemcitabine ; radiotherapy ; radiation myositis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 1523-1530 
    ISSN: 1569-8041
    Schlagwort(e): androgen-independent prostate cancer ; chemotherapy ; metastatic prostate cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background and purpose:A great number of clinical researchstudies have been reported in the field of chemotherapy for advancedandrogen-independent prostate cancer during the last ten years. The aims ofthe present review were to assess their impact on management of the diseaseand on survival of patients. Methods:The review of full published reports was facilited by theuse of a MEDLINE computer search. Results:Clinical research studies have focused on definingguidelines for eligibility criteria and accurate endpoints for patients to beenrolled onto clinical trials and developing new agents or combinationof drugs including estramustine phosphate. Any combination of currentchemotherapy has no impact on overall survival of patients. Among drugs indevelopment, only the promising activity observed with docetaxel deservesrandomized trials to assess its impact on survival. The major innovativeadvance of the 90s is the demonstration of the impact of chemotherapy(mitoxantrone + prednisone) on quality of life as compared to prednisonealone. A greater and longer-lasting improvement in quality of life along witha concomitant decrease in costs was observed. Conclusions:At the present time, chemotherapy should beconsidered as a palliative treatment in patients with symptomaticandrogen-independent disease. The enrollment of patients into clinical trialsdealing with quality of life as primary endpoint is strongly solicited. Astandard methodology should be used in phase II trials with a primary goal ofselection of agents which should progress to randomized trials using survivalas an endpoint. Hopefully new specific strategies targeted to reverse themolecular changes that underlie prostate tumorigenesis should rapidly impactthe multimodality management of AIPC in the third millenium.
    Materialart: Digitale Medien
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  • 10
    ISSN: 1569-8041
    Schlagwort(e): cancer ; chemotherapy ; pleuropulmonary blastoma ; PPB ; soft tissue sarcoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Pleuropulmonary blastoma (PPB) is a rare dysontogenetic tumor that usuallydevelops in the first decade of life and has been recognized as a distinctclinico-pathological entity different from the ordinary pulmonary blastoma ofadulthood. Since the tumor grows aggressively and tends to metastasize early,physicians have to be aware of late onset of symptoms and uncommonmanifestations. We report a case of PPB in a young adult and its recurrencein the pancreas after primary surgical treatment and adjuvant chemotherapy.Keeping in mind the moderate prognosis of PPB in children, accurate assessmentand treatment of PPB require a team approach of oncology, radiology andsurgery to establish new therapeutic guidelines in the future.
    Materialart: Digitale Medien
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  • 11
    ISSN: 1569-8041
    Schlagwort(e): 5-fluorouracil ; arterial access device ; chemotherapy ; colorectal cancer ; hepatic arterial chemotherapy ; liver metastases ; port-a-cath
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Hepatic arterial chemotherapy for liver metastases ofcolorectal cancer is still under discussion. Mainly because of the technicalcomplications of this mode of treatment and the lack of a survival benefit inrandomized studies. We performed an analysis of hepatic arterial5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at asingle institution. Patients and methods:One hundred forty-five patients withinoperable liver metastases from colorectal cancer were included. 5-FU, 1000mg/m2/day continuous infusion for five days every three weeks, wasdelivered in the hepatic artery by percutaneous catheter or arterial accessdevice. Results:The response rate was 34% for all patients,40% in patients with extrahepatic disease, and 15% in patientswith i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and14.3 months, respectively. In patients with extrahepatic disease or i.v.5-FU-based pretreatment, OS was significantly shorter compared to patientswithout extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 monthsand 10.1 vs. 17.4 months, respectively). forty-seven percent of patientsstopped treatment because of a complication. Complications most often seen inpatients with arterial ports were hepatic artery thrombosis (48%) anddislocation of the catheter (22%). Conclusions:The results of our analysis are in line with previousphase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment wereprognostic for reduced OS. The complication rate of hepatic arterial deliverywas worrisome, although, no negative impact on survival could be established.There is a strong need for improvement of hepatic arterial delivery methodsbefore further evaluation of hepatic arterial 5-FU will be worthwhile.
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  • 12
    ISSN: 1569-8041
    Schlagwort(e): advanced ovarian cancer ; chemotherapy ; docetaxel ; phase II trial
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:This phase II study was conducted to evaluate theefficacy and toxicity of docetaxel in Japanese patients with advanced ovariancancer. Patients and methods:Docetaxel was administered at a dose of 70mg/m2 intravenously to patients with platinum pre-treated advancedovarian cancer. Treatment was repeated every three weeks. No routinecorticosteroid premedication was given. Results:Ninety patients with advanced ovarian cancer were enteredand sixty were assessable for response. The overall response rate was28% in the assessable patients (95% confidence interval(95% CI): 17.5%–41.4%). CA125 responses were seenin 8 (24%) of 34 assessable patients for CA125 criteria. The 36platinum-refractory patients had a response rate of 25% compared with33% in the platinum-sensitive patients. The predominant toxicity wasneutropenia, with 86% of the patients experiencing grade 3 or 4.Hypersensitivity reactions occurred in 37% of the patients and were notlife threatening. Edema was mild and infrequent. Conclusion:Docetaxel at 70 mg/m2 demonstratedeffectiveness as a treatment of both platinum-sensitive andplatinum-refractory ovarian cancer patients, with a low incidence of severehypersensitivity reactions and edema.
    Materialart: Digitale Medien
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  • 13
    ISSN: 1569-8041
    Schlagwort(e): autologous stem-cell transplantation ; chemotherapy ; follicular lymphoma ; progression
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Among the 566 patients with follicular lymphomas (FL)included in the GELF 86 prospective trials from October 1986 to September1995, 372 with progressive/relapsing disease were analyzed retrospectively toidentify prognostic factors at first relapse. Patients and methods:For progressive FL, patients received mono-(22%) or polychemotherapy (78%) followed by high-dose therapy(HDT) with ASCT for 83 patients (22%). The median time toprogression from initial treatment was 23 months (range 3–102 months)and 24% of documented patients (52 of 217) had histologicaltransformation (HT). Salvage therapy produced an overall response in64% of patients and the five-year survival from progression was42%. Results:For patients who underwent HDT with ASCT compared tostandard treatment, five-year freedom from second failure was at 42%vs. 16% (P = 0.0001) and five-year survival was58% vs. 38% (P = 0.0005), respectively. Thebenefit of HDT and ASCT remained if we consider only patients less than 65years (five-year survival at 60% vs. 40%; P =0.001). Multivariate analysis of parameters significant according tounivariate analysis found that no ASCT at first progression, age at relapse〉50 years, progression on-therapy were adversely significant onsurvival. Conclusions:HDT with ASCT compared to standard treatmentprolonged remission and survival after first progression of FL patients.
    Materialart: Digitale Medien
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  • 14
    ISSN: 1569-8041
    Schlagwort(e): 5-fluorouracil ; chemotherapy ; colorectal cancer ; cost/effectiveness analysis ; irinotecan
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:It has been shown that irinotecan is superior toinfusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancerafter 5-FU failure. In a recent trial, median survival was 10.8 months forpatients treated with irinotecan, compared to 8.5 months in patients receivinginfusional 5-FU. Considering the statistically significant but clinicallyrelatively small advantage of irinotecan over 5-FU, cost effectiveness shouldalso be part of treatment decision. Purpose:To relate the costs of each management approach tooverall survival in patients with metastatic colorectal cancer. Patients and methods:The healthcare costs and medical benefits(treatment-added survival) of second-line chemotherapy in patients (infusional5-FU: 129, irinotecan: 127) were compared. Data on overall survival were drawnfrom a multicenter randomised trial that compared infusional 5-FU (continuousinfusion, AIO, or LV5-FU2 regimens) to irinotecan alone. Costs were derivedfrom the accounting system in two university hospitals in Paris, France. Results:The range in total healthcare costs was 14,135 to 12,192US$ patient between management approaches, with irinotecan chemotherapycosting most and 5-FU-continuous infusion least. If survival was included asa treatment benefit, the cost-effectiveness ratio of irinotecan over 5-FUranged from 9,344 to 10,137 US$ per year of added survival. Conclusions:The least expensive management for metastaticcolorectal was 5-FU infusion but the additional cost of irinotecan wasbalanced by the added months of survival, with a cost-effectiveness ratioclose to that of other cancer treatments.
    Materialart: Digitale Medien
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  • 15
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 81-85 
    ISSN: 1569-8041
    Schlagwort(e): ABVD ; BEACOPP ; chemotherapy ; clinical trials ; COPP ; dose intensification ; Hodgkin's disease ; radiotherapy ; risk factors
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Treatment strategies in Hodgkin's disease (HD) arechanging fundamentally over the last decades. Both radiotherapy andcombination chemotherapy are effective treatment modalities. However, theoptimal choice of treatment or combinations of treatment is still debated fordifferent prognostic groups. Patients and methods:The German Hodgkin's Lymphoma Study Group(GHSG) initiated randomized clinical trials since 1978. Over the past 20years, more than 6000 patients with HD in all stages were randomized, treatedand followed by the GHSG. Patients are now being recruited from more than 300clinical centers. Results:As a consequence of different clinical trials, it is nowthe policy of the GHSG to tailor treatment to the individual risk of patients,giving favorable patients less intensive and less toxic therapy thanunfavorable patients. The treatment for early and intermediate stage HDbecomes quite similar with few cycles of polychemotherapy followed by involvedfield irradiation. In advanced stage HD, the introduction of dose intensifiedchemotherapy (BEACOPP), has improved treatment results and thus willsubstitute the MOPP or ABVD regimens. Conclusions:Although most of the patients with HD will be curedby modern treatment stategies, several questions are still subjects of ongoingclinical trials: 1) which chemotherapy regimen in which quantity will be thebest with respect to efficacy and toxicity and 2) which dose and field sizeof radiotherapy is adequate within the combined modality.
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  • 16
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; docetaxel ; gastric cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose:A multi-centric trial was performed to explore theclinical activity, in terms of response and toxicity (primary objectives),duration of response and survival (secondary objectives), of docetaxel withcisplatin in advanced gastric cancer (AGC). Patients and methods:Patients with measurable unresectable and/ormetastatic gastric carcinoma, performance status ≤1, normal hematological,hepatic and renal functions and not pretreated for advanced disease bychemotherapy received up to eight cycles of TC (docetaxel 85 mg/m2d1, cisplatin 75 mg/m2 d1) q3w. Dose escalation to 100mg/m2 was performed in five patients and was discontinued forexcessive toxicity. Results:Forty-eight patients were accrued. A median of 5cycles/patient was given. We observed 2 complete and 25 partial responses foran overall intent to treat response rate of 56% (95% CI:41%–71%). Twelve patients had stable disease for ≥9weeks (3 cycles). The median time to progression and overall survival were 6.6and 9 months, respectively. Grade ≥3 toxicities were neutropenia81%, anemia 32%, thrombocytopenia 4%, alopecia36%, fatigue 9%, mucositis 9%, diarrhea 6%,nausea/vomiting 4%, neurologic 2%, and one anaphylaxisprecluding treatment administration. We recorded nine episodes of non-fatalfebrile neutropenia in eight patients, two of them with docetaxel at 100mg/m2. There were no direct treatment-related deaths. Conclusions:TC is active in AGC with a high response rate in amulticentric trial. Despite its hematotoxicity, this regimen is well toleratedand can be recycled as originally planned in 78% of the cases. Theseresults may serve as basis for further developments of docetaxel containingregimens in this disease.
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  • 17
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; concomitant chemoradiotherapy ; head and neck cancer ; paclitaxel ; radiation ; reirradiation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Concomitant chemoradiotherapy is an effectivetreatment modality for advanced head and neck cancer, but improved regimensare needed. We sought to define the toxicities, recommended phase II dose, andoutcome of a combination chemotherapy regimen with concomitanthyperfractionated radiotherapy in patients with poor prognosis cancers of thehead and neck, including those having received prior curative intentradiotherapy. Patients and methods:From 1995 until 1997, 54 patients weretreated, 25 of whom had received a prior full course of radiotherapy to thehead and neck. Patients were treated with 5-fluorouracil (5-FU) 600mg/m2/day continuous infusion × 5 days (days 1–5),hydroxyurea, 500 mg p.o. bid × 11 doses (days 1–6) and paclitaxel(60–150 mg/m2) by one-hour infusion on day 2 using a doseescalation strategy. Radiotherapy was given concomitantly on days 2–6,150 cGy bid. Each of 4–5 cycles was delivered every other week. Results:The MTD of paclitaxel was 100 mg/m2. Theregimen was feasible; radiotherapy was delivered at a median of 7300 cGy and83% of patients received ≥80% planned dose intensity.Hematological toxicity, with granulocyte colony stimulating factor, was verymild. Dose limiting toxicities were mucositis and dermatitis. Despite poorprognosis, two-year survival was 45%. Conclusions:The recommended phase II dose of this regimen is 5-FU600 mg/m2/day × 120 hours (days 1–5), hydroxyurea 500mg p.o. b.i.d. × 11 doses (days 1–6), paclitaxel 100mg/m2 over one hour on day 2, and radiotherapy 150 cGy b.i.d. days2–6. Concomitant chemotherapy and re-irradiation was feasible on thisprotocol and resulted in long-term survival in patients without other curativeintent options.
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  • 18
    ISSN: 1569-8041
    Schlagwort(e): alkylating agents ; bendamustine ; chemotherapy ; phase I study ; solid tumours ; weekly chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:The cytotoxic agent bendamustine combines apurine-like benzimidazol and alkylating nitrogen mustard group. The clinicallytolerated dose for single bolus bendamustine is 215 mg/m2, forfractionated therapy on four consecutive days 85 mg/m2. The maximumtolerated dose of a day 1 and 8 (q4w) 30 min infusion schedule was recentlyfound to be 160 mg/m2, mouth dryness and fatigue weredose-limiting. Our current phase I trial was designed to define therecommended dose of a new weekly short infusion schedule. Patients and methods:Patients with refractory malignant tumoursqualified for the trial after written informed consent was obtained.Bendamustine was given as a 30-min i.v. infusion weekly for up to eightconsecutive weeks. Results:Twelve patients (8 male, 4 female, median age 57.5 years,range 42–64) were enrolled in this trial. At the starting dose of 80mg/m2, two patients had dose-limiting toxicity (fatigue grade 3,mouth dryness grade 3, fever grade 4 Common Toxicity Criteria). Nodose-limiting events were observed in six patients treated at 60mg/m2. An intermediate dose level of 70 mg/m2 wasstudied in three younger, less heavily pre-treated patients, was welltolerated and not associated with dose-limiting events. Haematologicaltoxicity was mild except for grade 3–4 lymphocytopenia, occurring in 11of 12 patients. Bendamustine was found to induce long-lastingpanlymphocytopenia with predominant B-cell cytotoxicity. Conclusions:The maximum tolerated dose of weekly bendamustinegiven as a 30-min i.v. infusion is 80 mg/m2, mouth dryness, fatigueand fever are dose-limiting. The recommended dose for phase II trials is 60mg/m2.
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  • 19
    ISSN: 1569-8041
    Schlagwort(e): anthracycline ; chemotherapy ; liposomal daunorubicin ; lymphoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Standard therapy for lymphoma consists of acyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP)combination regimen. Liposomal daunorubicin (DaunoXome®) is an alternativeto doxorubicin for patients with lymphoma because of its more favorable safetyprofile and potentially more selective uptake in lymphoma. The objectives ofthis study were to determine the maximum tolerated dose (MTD) of liposomaldaunorubucin with CVP (COP-X) and the tolerability of the regimen in patientswith indolent lymphoma. Patients and methods:Patients with low-grade andintermediate-grade lymphoma having adequate cardiac, hepatic, and renalfunction were enrolled. Patients received C 750 mg/m2, V 1.4mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50–100mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1–5. MTD wasthe liposomal daunorubicin dose associated with 20% dose-limitingtoxicity (ANC 〈500/mm3 for 〉5 days or febrile neutropenia). Results:Twenty patients, median age 59 years, were treated. Theliposomal daunorubicin MTD combined with CVP was 70–80 mg/m2,depending on patient population. No significant non-hematologic toxicityoccurred. Response rate was 44% (2 complete and 5 partial responses). Conclusions:A liposomal daunorubicin dose of 80 mg/m2in the COP-X regimen was well tolerated with little non-hematologic toxicity.
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  • 20
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; chromosome aberrations ; malignant germ-cell tumours
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 21
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 11-16 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gene therapy ; head and neck cancer ; immunotherapy ; radiotherapy ; recurrent ; surgery
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Locoregional recurrence is the most common cause of failure after head andneck cancer surgery. It is a disease which causes significant morbidityespecially on speech and swallowing. There are many different treatmentsavailable including surgery, reirradiation and chemotherapy. However, none ofthese have produced any significant survival benefit. Because of this, therehas been considerable interest in the development of new biological therapiessuch as gene therapy and immunotherapy for this disease. The objectives ofthis article are to provide an overview of the currently available therapiesfor recurrent head and neck cancer including gene therapy and immunotherapy.Prevention of recurrent disease by the detection and treatment of minimalresidual disease is also discussed.
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  • 22
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; hepatocellular carcinoma ; liposomal doxorubicin ; phase II
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Pegylated liposomal doxorubicin has an enhancedefficacy and reduced toxicity compared with free doxorubicin. The efficacy andtoxicity of pegylated liposomal doxorubicin was investigated in patients withhepatocellular carcinoma. Patients and methods:Patients with histologically confirmed,locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index〉60% were included in this prospective single-arm study. Exclusioncriteria were liver cirrhosis stage Child–Pugh C, previous chemotherapy,or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of30 mg/m2 every three weeks until progression of disease. Afterinclusion of five patients the dose could be escalated to 40 mg/m2in absence of toxicity grade 3 and 4. Results:Sixteen patients were evaluable for response. Noobjective response was achieved. The median survival time was 140 days(95% confidence interval: 126–154 days). Treatment toxicitiesgrade ≥3 comprised increased liver enzymes in patients with preexistinggrade 1 or 2 elevation (n = 6), hematologic toxicity (n =5), and hypersensitivity (n = 2). Conclusions:Pegylated liposomal doxorubicin is not effective fortreatment of advanced hepatocellular carcinoma. The favorable toxicity profilewas confirmed even in patients with underlying liver disease.
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  • 23
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gemcitabine ; non-small-cell lung cancer ; paclitaxel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Thirty patients with chemotherapy-naïve advanced non-small-cell lungcancer (NSCLC) were given escalating doses of paclitaxel (150, 175, 200mg/m2) on day 1 in three consecutive cycles, together with a fixeddose of gemcitabine 1000 mg/m2 on days 1 and 8; cycles wererepeated every three weeks. The dose escalation of paclitaxel was feasible inthe majority of patients. Subsequently, 30 other NSCLC patients received adose of 200 mg/m2 paclitaxel with gemcitabine 1000 mg/m2in a phase II study. The major side effect was mild myelosuppression. Aresponse rate of 24% was achieved in 49 fully evaluable patients. Thisregimen proved to be safe and easy to administer on an out-patient setting,and constitutes now one of the arms of the current EORTC randomized study foradvanced NSCLC.
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  • 24
    ISSN: 1569-8041
    Schlagwort(e): 5-fluorouracil ; antifolates ; apoptosis ; DNA repair ; p53 ; thymidylate synthase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been usedas a target for cancer chemotherapy in the development of fluoropyrimidinessuch as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novelfolate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331,LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331.Although TS has been considered as a target for chemotherapy, the precisemechanism by which TS inhibition leads to cell death is still not completelyresolved. TS inhibition results in depletion of dTTP, an essential precursorfor DNA, and an increase in dUTP. This results in the so-called thymine-lessdeath due to misincorporation of dUTP into DNA; its excision, catalysed byuracil-DNA glycosylase, results in DNA damage. Both this imbalance indTTP/dUTP and DNA damage can result in induction of downstream events, leadingto apoptosis. On the other hand a specific interaction exists betweenoncogenes and TS, by binding of TS protein to the p53and c-mycRNA, while wt p53can also inhibit TS promotor activity. TSinhibition by either 5-FU or antifolates can also result in a depression ofTS protein mediated inhibition of TS mRNA translation leading to induction ofmore TS protein synthesis, and p53protein may further deregulatethis process. These complex indirect and direct interactions between oncogenesand TS may have as yet unclear clinical implications, since most data arebased on in vitroor in vivo studies and some results arecontradictive. In some preliminary clinical studies evidence was postulatedfor a combined prognostic role for TS and p53.This knowledge shouldbe used to design clinical studies with the aim to deliver effective treatmentto potentially sensitive patients both in the adjuvant setting and in advancedstage disease.
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  • 25
    ISSN: 1569-8041
    Schlagwort(e): breast cancer ; carboplatinum ; chemotherapy ; continuous 5-fluorouracil
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We performed a trial using the combination of epirubicin 50mg/m2/day 1, carboplatinum AUC 5/day 1 and continuous5-fluorouracil (5-FU) 200 mg/m2/day (every 4 weeks for6 months) to confirm the efficacy and low toxicity profile of thisregimen in breast cancer. In 51 patients with metastatic(n = 33) or locally advanced (n = 18)breast cancer the overall response rate was 86% (95% confidenceinterval (95% CI): 73%–94%): 94% in locallyadvanced and 81% metastatic disease. Grade 3–4 toxicity was low:4% of patients presented with febrile neutropenia, 16% withsevere palmar-plantar syndrome, 10% with Port-a-cath thrombosis. This study confirms the high efficacy of infusional 5-FU-based regimens andjustifies further research into novel promising oral 5-FU derivatives.
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  • 26
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; ovarian cancer ; second-line
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Gemcitabine is active in patients with otherwiseresistant or refractory ovarian cancer. As the drug is well tolerated, studiesusing gemcitabine combined with other antineoplastic agents are needed. Theaim of the study was to determine the maximum tolerated dose (MTD) ofepirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methods:Patients with platinum-resistant orrefractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800mg/m2 day 1 and 8; 200 mg/m2 escalation per level) andepirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2escalation per level) were given every 21 days for four to six cycles. G-CSF(filgrastim 5 µg/kg/die) was given in case of grade 4 neutropenia(levels without support) or from day 9 up to leukocyte count〉10,000/mm3 after nadir (levels with support). Cohorts of threepatients were enrolled at each level, and another three patients were planned,if one dose-limiting toxicity (DLT) was registered. MTD was determined firstwithout and then with G-CSF. Results:Four levels were studied (G 800 + E 60; G 1000 + E 60;G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and threepatients enrolled, respectively. DLT (grade 4 febrile neutropenia) wasobserved in two patients at level 3. Thus, G1000 + E 60 mg/m2 wasthe MTD without G-CSF. The addition of prophylactic G-CSF did not allow afurther increase of the dose and grade 4 thrombocytopenia was the DLT at level4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in fourpatients. Among the 13 patients with measurable or evaluable disease, 3partial responses were observed for an overall response rate of 23.1%. Conclusions:The combination of gemcitabine 1000 mg/m2(day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasibletherapy. Grade 4 neutropenia is frequent and G-CSF support is often required.With prophylactic support of G-CSF, the DLT is thrombocytopenia.
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  • 27
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; intra-arterial ; liver metastasis ; unresectable pancreatic cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:A phase II trial of a new intra-arterial chemotherapyregimen for unresectable pancreatic cancer (UPC). Patients and methods:Ninety-six patients with UPC were treatedwith intra-arterial chemotherapy at three-weekly intervals. The schedule usedwas FLEC: 5-fluorouracil 1000 mg/m2, folinic acid 100mg/m2, carboplatin 300 mg/m2; epirubicin 60mg/m2. Results:The overall response rates by CT-scan evaluation were:15% partial response (PR), 44% stable disease (SD), 17%progressive disease (PD). The overall median survival was 9.9 months, and 10.6and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in42% of patients. A weight gain 〉7% from baseline occurred in8% of patients. A total of 341 courses of FLEC were administered. Grade3–4 hematological toxicity was seen in 25% of patients;ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; andgrade 3 alopecia in 16%. One sudden death, a pre-infarction angina, anda transitory ischemic attack were observed. The only complication related tothe angiographic procedure was an intimal dissection of the iliac artery. Conclusions:The intra-arterial FLEC regimen was well toleratedand active. It requires only one day of hospitalization. Efficacy could onlybe assessed in a randomized study against a gemcitabine containing regimen.
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  • 28
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; combination ; etoposide ; ifosfamide ; ovarian cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:The prognosis of platinum resistant ovarian cancer isvery poor and the treatment of choice has not been clearly defined. Patients and methods:We conducted a phase II study with thecombination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) andetoposide per os at 100 mg daily (days 1–10) every four weeks. To beeligible for the study patients had to be resistant to platinum and paclitaxelpretreated. Results:Forty-one patients entered the study. The median intervalfrom the previous chemotherapy was 3.9 months. The median number of previouschemotherapeutic regimens was 2. Severe toxicities included neutropenia(41% of patients), leukopenia (29%) and thrombocytopenia(13%). Thirty-five patients are assessable for response. Nine patientsresponded (22% of the eligible, 26% of the assessable), four ofthemdemonstrated complete response to chemotherapy (10% and 12%,respectively), while three patients demonstrated stabilization of theirprogressive disease. After a median follow-up of 18 months, time toprogression is 3 months (range 0.9–14.4), duration of response is 9months (2.5–11) and median survival is 13 months (2.5–37.4+). Conclusions:The combination of ifosfamide with oral etoposideappears to have significant but manageable toxicity and encouraging efficacyin platinum resistant ovarian cancer.
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  • 29
    Digitale Medien
    Digitale Medien
    Springer
    Virus genes 20 (2000), S. 143-147 
    ISSN: 1572-994X
    Schlagwort(e): equine arteritis virus ; cell infection ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Equine arteritis virus (EAV) is the etiological agent of equine viral arteritis, a contagious viral disease of equids. EAV is the prototype virus of the arteriviruses, a group of small enveloped viruses with positive single-stranded RNA genomes. Because apoptosis or programmed cell death is believed to play an important role in the biogenesis of several cytopathogenic viruses, we examined whether EAV was able to induce cell apoptosis in vitro. To do this, Vero cells were infected with EAV at a multiplicity of infection of 0.1 tissue culture infectious dose (TCID50) per cell, and analyzed at various time intervals for the appearance of apoptotic signs. Fragmentation of chromosomal DNA into nucleosomal oligomers and caspase activation were observed in the infected cells at the time (e.g. 24 h postinfection) where a noticeable cytopathic effect was observed. The kinetics of the DNA fragmentation correlated with that of the production of progeny virus, so that viral multiplication was not interrupted by the apoptotic cell damage. All these data provide evidence that EAV is able to induce apoptotic cell death in vitro.
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  • 30
    Digitale Medien
    Digitale Medien
    Springer
    Virus genes 21 (2000), S. 13-25 
    ISSN: 1572-994X
    Schlagwort(e): adenovirus E3 proteins ; E3 protein sequence comparison ; immune evasion ; interference with antigen presentation ; CD95 (Fas/APO-1) ; apoptosis ; receptor down-regulation ; TNF mediated lysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Persistent viruses have evolved multiple strategies to escape the host immune system. One important prerequisite for efficient viral reproduction in the face of an ongoing immune response is prevention of premature lysis of infected cells. A number of viruses achieve this goal by interfering with antigen presentation and recognition of infected cells by cytotoxic T cells (CTL). Another viral strategy aims to block apoptosis triggered by host defense mechanisms. Both types of strategies seem to be realized by human adenoviruses (Ads). The early transcription unit E3 of Ads encodes proteins that inhibit antigen presentation by MHC class I molecules as well as apoptosis induced by tumor necrosis factor α (TNF-α) and Fas ligand (FasL). Here, we will describe the organization of the E3 regions of different Ad subgroups and compare the structure and functions of the known immunomodulatory E3 proteins.
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  • 31
    Digitale Medien
    Digitale Medien
    Springer
    Virus genes 21 (2000), S. 97-109 
    ISSN: 1572-994X
    Schlagwort(e): myxoma virus ; immuno-modulator ; viroceptor ; TNF receptor ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Myxoma virus, a member of the poxvirus family of DNA viruses, encodes many virulence factors to combat and evade the host immune responses. Among the virus-encoded immuno-modulators is M-T2, a tumor necrosis factor receptor (TNF-R) homologue. M-T2 is secreted as monomeric and dimeric species that bind and inhibit rabbit TNF in a species-specific manner. Deletion analysis indicates that the anti-TNF function is mediated by the first three of four cysteine rich domains (CRDs) of M-T2. In addition, the intracellular form of M-T2 has the ability to block virus-induced apoptosis in lymphocytes, and the first two CRDs appear to be sufficient for this function. Although the mechanisms for the anti-TNF and anti-apoptotic functions of M-T2 are not yet fully defined, we postulate that these dual activities of M-T2 are mediated through different functional motifs and abrogate distinct cellular responses to virus infection.
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  • 32
    Digitale Medien
    Digitale Medien
    Springer
    Virus genes 21 (2000), S. 51-64 
    ISSN: 1572-994X
    Schlagwort(e): apoptosis ; bZIP ; coiled body ; herpesvirus ; Jun ; nucleolus ; oncogene ; transactivation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract In order to adapt to and to cope with an often hostile host environment, many viruses have evolved to encode products that are homologous to cellular proteins. These proteins exploit the existing host machinery and allow viruses to readily integrate into the host functional network. As a result, viruses are able to maneuver their journey seemingly effortlessly inside the host cell to achieve ultimate survival. Such molecular mimicries sometime go overboard, allowing viruses to overtake the cellular pathways or evade the immune system as do many of the retroviral oncogenes. Retroviral oncogenes are derived directly from host genes, and they are virtually identical to host genes in sequences except those mutations that make them unregulatable by host. Oncogenic herpesviruses also encode oncogenes, or transforming genes, which have independently evolved and are distantly related to host genes. However, these genes do share consensus structural motifs with cellular genes involved in cell growth and apoptosis and are functional analogues to host genes. The Marek's disease virus oncoprotein, MEQ, is one such example. MEQ is a basic region-leucine zipper (bZIP) transactivator which shares extensive homology with the Jun/Fos family of transcription factors within the bZIP domain, but not in other regions. Like all other bZIP proteins, MEQ is capable of dimerizing with itself and with a variety of bZIP partners including c-Jun, B-Jun, c-Fos, CREB, ATF-1, ATF-2, and SNF. MEQ-Jun heterodimers bind to a TRE/CRE-like sequence in the meq promoter region and have been shown to up-regulate MEQ expression in both chicken embryo fibroblasts and F9 cells. In addition, the bZIP and transactivation domains are interchangeable between MEQ and c-Jun in terms of transforming potential; i.e. MEQ can functionally substitute for c-Jun. These properties enable MEQ to engage in host cell processes by disguising itself as c-Jun. On the other hand, there are properties of MEQ notably different from c-Jun, which include its capability to bind RNA, to bind a CACAC-bent DNA structure as a homodimer, to inhibit apoptosis, and to interact with CDK2. MEQ’s subcellular localization in the nucleolus and coiled body, is also different from Jun/Fos family of transactivators. These unique features may provide the MEQ with additional facility in regulating MDV replication, establishing latency, and cellular transformation. In this review, we will attempt to summarize the past research progress on MDV meq, with a focused on the similarities and differences between MEQ and cellular proteins, and between MEQ and other viral oncoproteins.
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  • 33
    Digitale Medien
    Digitale Medien
    Springer
    Journal of gastroenterology 35 (2000), S. 907-911 
    ISSN: 1435-5922
    Schlagwort(e): Key words: gastric cancer ; liver neoplasms ; secondary ; interventional radiology ; chemotherapy ; chemoembolization ; therapeutic
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract: Little is known about the effectiveness of transcatheter chemotherapy in liver metastases from gastric cancer. The aim of this study was to evaluate the initial results of hepatic artery infusion and oily chemoembolization in these liver secondaries. Courses of transcatheter arterial infusion with 5-fluorouracil/doxorubicin (12 patients) and oily chemoembolization with doxorubicin-in-iodized oil and gelatin sponge (12 patients) were performed in 24 patients with histologically proven unresectable gastric cancer liver metastases. A positive effect of treatment (partial response + stabilization) was seen in 92% of the patients after chemoinfusion and in 50% after chemoembolization. The 1- and 2-year actuarial survival rates were 92% and 53% for infusion vs 50% and 17% for chemoembolization, respectively (log-rank test, P = 0.0009). For patients who had already died, the mean survival was 19.2 months vs 9.5 months (Student's t-test, P 〈 0.05) with median survivals of 23 months vs 8 months, respectively. The results with arterial infusion were very close to those reported for liver resection. Transcatheter therapy appears to be useful for the palliation of unresectable liver metastases from gastric cancer. If regional chemotherapy is used, arterial infusion should be the first-choice treatment, with oily chemoembolization being reserved for patients who do not respond to infusion.
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  • 34
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 927-937 
    ISSN: 1569-8041
    Schlagwort(e): brain lymphomas ; chemotherapy ; intrathecal chemotherapy ; methotrexate ; primary central nervous system lymphoma ; radiotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Primary central nervous system lymphomas (PCNSL) are aggressivemalignancies, exhibiting one of the worst prognoses among lymphomas. The besttreatment modality for PCNSL has not yet been identified. Several therapeuticquestions still remain unanswered, and some methodological pitfalls inclinical trials prevent definitive conclusions from being drawn. In thisreview, certain aspects of trial design as well as emerging therapeuticguidelines are analyzed, and future perspectives are discussed. In the vast majority of prospective trials, general criteria for treatmentof aggressive lymphomas were adopted, choosing primary chemotherapy (CHT)followed by radiotherapy (RT) as therapeutic modality. This strategy produceda five-year survival of 22%–40% in comparison to the3%–26% reported with RT alone. Systemic high-dosemethotrexate (HD-MTX) seems to be the most effective drug, producing aresponse rate of 80%–90% and a two-year survival of60%–65%. To date, the addition of other drugs atconventional doses have not consistently improved outcome. With a fewexceptions, any regimen without HD-MTX comprehensively performed no betterthan RT alone. In combined treatment, RT doses should be decided on the bases of responseto primary CHT and the number of lesions, and, until definitive conclusionsfrom well-designed trials are available, RT parameters should follow thewidely accepted principles used for other aggressive lymphomas. CHT asexclusive treatment, keeping RT for relapses or persistent disease, appearsto be an attractive strategy. However, the worldwide experience with thismodality is still limited, and corroborating data are needed. Intrathecal CHTstill has not found a defined role in PCNSL management. Preliminary data seemto indicate that adequate meningeal treatment with HD-MTX, but withoutintrathecal CHT, could also be suitable in positive-cerebrospinal fluidpatients. Future efforts should be addressed to identify new active drugs and moreefficient CHT combinations, to evaluate the efficacy of high-dose CHTsupported by autologous peripheral blood stem cells transplantation, and toclarify the impact of RT delay in complete responders, the usefulness ofintrathecal CHT, and the best management for elderly patients. The assessmentof impact of treatment on neuropsychological functions and quality of life isa mandatory endpoint in clinical trials.
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  • 35
    ISSN: 1569-8041
    Schlagwort(e): antifolate ; chemotherapy ; pancreatic cancer ; thymidylate synthase inhibitor
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose:To determine the safety and activity of LY231514(ALIMTA™, MTA, pemetrexed disodium, Eli Lilly and Co.,Indianapolis, IN) in chemotherapy-naïve patients with advanced pancreaticcancer. Patients and methods:Patients with unresectable or metastaticpancreatic cancer received LY231514 600 mg/m2 as a 10–minuteinfusion every three weeks. Results:Forty-two patients were enrolled in this phase II trial.The median age was 60.3 (range 37–77) years; 79% had metastaticdisease. Neutropenia was common (40% of patients ≥ grade 3) butinfectious complications were rare. Significant anemia or thrombocytopeniaoccurred in 〈20% of patients. Non-hematologic toxicities includedgrade 2 or 3 skin reaction which was ameliorated by dexamethasone. Elevationsof bilirubin or transaminases were infrequent (〈25% of patients) anddid not require dose reductions or treatment delays. Thirty-five patientsreceived two cycles of therapy and were evaluable for response. One complete(duration 16.2 months) and one partial (duration 6.9 months) were observedresulting in an objective response rate of 5.7% for evaluable patients.In addition, 17 patients (40%) had stable disease that lasted ≥6months in 5 patients. The median survival was 6.5 months, with 28% ofpatients alive at one year. Conclusions:LY231514 is a well-tolerated agent with minimalobjective antitumor activity in pancreatic cancer. The median and one yearsurvival times, which may be important indicators in phase II trials of newagents, are of interest. Combination trials of LY231514 in pancreatic cancerare planned.
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  • 36
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; doxorubicin ; hepatocellular carcinoma ; liposome ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:There is lack of effective and safe chemotherapy foradvanced hepatocellular carcinoma. Polyethylene glycol-coated (pegylated)liposomal doxorubicin (PLD) has long circulation time and enhanced drugaccumulation in the tumor tissues. It has significant activity in Kaposi'ssarcoma, breast and ovarian cancers and the acute adverse effects of free drugare reduced. Patients and methods:A patient with advanced hepatocellularcarcinoma was treated with PLD and a pharmacokinetic study was performed.Initial serum total and direct bilirubin were 3.6 and 6.8 folds of uppernormal, respectively, and an indocyanine green clearance test at 15 minuteswas 26.3% (normal 〈 15%). Results:Compared to cases with normal liver function, increasedvolume of distribution of doxorubicin correlated with a large amount ofascites (P〈 0.05). The clearance of drug was unexpectedly higherthan in cases with normal liver function (P〈 0.05). According tothe pharmacokinetic studies, the disposition of PLD in this case has not beenretarded even in the presence of severe liver dysfunction. Only minimaltoxicities including grade 2 stomatitis and moderate leukopenia were observed.The tumor had a partial remission and the patient survived nine months afterPLD treatment. Conclusion:PLD could serve as a safe and effective treatment forhepatocellular carcinoma even in the presence of impaired liver function. Itsrole in treating advanced hepatocellular carcinoma is worthy of further study.
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  • 37
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gemcitabine ; non-small-cell lung cancer ; phase II trial ; vinorelbine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose:The purpose of the present phase II trial was todetermine the efficacy and toxicity of vinorelbine–gemcitabine inpatients with advanced non-small-cell lung cancer (NSCLC). Patients and methods:From December 1997 to February 1999, 78chemotherapy-naive patients (median age 60 years, Karnofsky performance statusof 100, 90, 80 and 70 present in 5%, 41%, 36% and18% of the patients, respectively) with stage IIIB (17%) or IV(83%) NSCLC (65% adenocarcinomas, 22% squamous-cellcarcinomas, 10% large-cell carcinomas, 3% mixed-cell carcinomas)received 25 mg/m2 vinorelbine and 1200 mg/m2 gemcitabineon days 1, 8 and 15 of a four-week cycle. Results:In an intent-to-treat analysis, partial responses wereseen in 19% of the patients. The median duration of response was 4.4months. The median survival time was seven months and the one-year survivalrate was 32%. Myelosuppression was the main side effect with WHO grade3/4 neutropenia and thrombocytopenia in 35% and 11% of thepatients, respectively. Other side effects were usually mild to moderate. Conclusions:Vinorelbine–gemcitabine is active, welltolerated and easy to administer on an outpatient basis in advanced NSCLC.Thus a randomized comparison of this combination with platinum-based protocolsis warranted in patients with advanced NSCLC.
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  • 38
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; esophageal cancer ; gemcitabine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:There were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,–difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer. Patients and methods:A total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30–60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles. Results:Gemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3–4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients. Conclusions:At the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.
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  • 39
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 957-960 
    ISSN: 1573-8221
    Schlagwort(e): human T lymphocytes ; staphylococcal enterotoxin B ; nitric oxide ; proliferation ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Abstract The involvement of nitric oxide (NO) in the regulation of human T cell response to bacterial superantigen (staphylococcal enterotoxin B) was studied. It was shown that stimulated T lymphocytes are the main source of NO. This superantigen markedly increased NO production and triggered the proliferative response of mononuclear cells from healthy individuals; the degree of apoptosis was low. In patients with purulent surgical diseases with high spontaneous and induced NO production, superantigen enhanced apoptosis of lymphocytes and induced anergy of T cells to enterotoxins. Increasing the concentration of NO in cultured cells from healthy individuals in the presence of NO donors also stimulated apoptosis and inhibited proliferative activity. These data suggest that NO regulates T lymphocyte response to superantigens. The increased production of NO probably contributes to the development of immunosuppression during bacterial infection.
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  • 40
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 892-894 
    ISSN: 1573-8221
    Schlagwort(e): immune deficiency ; apoptosis ; lymphocytes ; neoplasms and autoimmune diseases
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Abstract CD95 expression on peripheral blood lymphocytes in patients with neoplasms was higher than in patients with autoimmune disorders. Apoptosis of T cells increased during tumor growth. The data suggest that neoplasms are accompanied by more severe immune dysfunction than autoimmune disorders.
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  • 41
    Digitale Medien
    Digitale Medien
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 912-916 
    ISSN: 1573-8221
    Schlagwort(e): whole-body hyperthermia ; hepatocytes ; alkaline dissociation of tissues ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Abstract hyperthermia caused hemodynamic disorders in the liver and degenerative and necrobiotic changes in hepatocytes of CBA mice. Total hepatocyte count decreased during restitution, this decrease being most pronounced 30 min after exposure. The number of binucleated cells also markedly decreased. The absence of necrotic changes in hepatocytes during the entire restitution period indicated their apoptotic death and elimination by macrophagal resorption. Under these conditions liver regeneration at the cellular level occured mainly via division of binucleated hepatocytes. On the other hand, proliferation of oval cells in the portal zones and their differentiation into hepatocytes were observed at certain stages of reparative regeneration of the liver.
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  • 42
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 133-149 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; dose ; dose-density ; dose-intensity ; high-dose chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Shortening the interval between cycles is one meansof increasing the dose intensity of chemotherapy, and can be supported bybiological and mathematical rationales. Our objective was to assess theclinical relevance of the rapid repetition of regimens (so-called `dose-densechemotherapy') in various solid neoplasms. Design:The medical literature was reviewed in accord withMulrow's recommendations. Randomised studies comparing frequently-repeatedchemotherapy to standard regimens as well as open studies are described andcritically examined. Results:Dose-dense regimens were widely found to be feasible. In small-cell lung cancer, survival of patients receiving dose-denseregimens was better than that of patients treated by standard chemotherapy inthree trials, two of which reached significance, when these intensive regimensallowed better dose intensity. In poor-prognosis germ-cell tumors, a dose-dense regimen was not betterthan standard therapy, perhaps because of an excessively high toxicity-relateddeath rate. However, recent phase II studies have provided encouragingresults. In early breast cancer, the one published randomized study in the adjuvantsetting showed only a trend towards better disease-free survival innode-positive women receiving a weekly-repeated regimen. Two randomized trialsfailed to show any benefit in the neoadjuvant setting with a dose-denseregimen. No evidence of a benefit was provided in metastatic breast cancer. In advanced colorectal cancer, evidence of an improvement in survival withweekly or bi-weekly 5-FU–leucovorin compared to a classic monthlyschedule has recently been shown in two randomized trials, and dose-denseregimens are recognized as standard therapy in many countries. Phase II studies of dose-dense regimens have also shown high response ratesand long survival in many neoplasms, including Ewing's sarcoma, gestationaltrophoblastic disease, ovarian carcinoma and gastric cancer. Conclusions:A considerable amount of experience has been gainedwith frequently-repeated regimens. A few randomized trials have demonstrateda benefit for survival on standard chemotherapy in small-cell lung cancer andadvanced colorectal cancer. However, this benefit appears to be weak. Thecombination of dose-dense chemotherapy regimens with new anti-cancerstrategies based on our insights into the mechanisms of oncogenesis is achallenge on the eve of the millennium.
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  • 43
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; colorectal cancer ; oxaliplatin ; phase II
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Backround:Oxaliplatin is a novel platinum derivative, which,combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstratessynergistic activity in metastatic colorectal cancer (MCC). The HeCOGperformed a multicenter phase II study of a weekly oxaliplatin administrationschedule in patients with previously treated MCC to evaluate the antitumorefficacy and toxicity of this combination. Patients and methods:Eligible patients included those whorelapsed after or during chemotherapy with 5-FU and FA and/or irinotecan.Prior radiotherapy was accepted provided that measurable disease was outsidethe radiation fields. Other eligibility criteria included written informedconsent, a WHO performance status ≤2 and adequate bone marrow, liver andrenal function. Treatment consisted of Oxaliplatin 50 mg/m2 bytwo-hour intravenous (i.v.) infusion followed by FA 500 mg/m2(two-hour i.v. infusion) and 5-FU 2500 mg/m2 (24-hour continuousi.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every50 days. Results:Thirty-two patients (Median age 61 years, range25–76) entered the trial. The majority (75%) had progressed afterreceiving first-line chemotherapy. Diarrhea was the main non-hematologic toxicity. More than half of thepatients (53%) developed grades 3 or 4 diarrhea. Due to this sideeffect only 29% of cycles were given with at least 90% of theplanned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia andthrombocytopenia (10% for each), and grade 4 thrombocytopenia(3%). Two patients (6%) died of sepsis, one related toneutropenia and one due to urinary tract sepsis. Sixteen patients (50%)developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy,which was mild and transient. The objective response rate was 13%(95% CI: 3%–29%). All four responses were partial.Twelve patients (38%) had stable disease and 8 (25%) progressivedisease. The median time to progression was three months and the mediansurvival was nine months from the start of therapy. The Kaplan–Meierestimated probability of one-year survival for the group as a whole was32%. Conclusions:The weekly administration of oxaliplatin with 5-FUand FA was associated with considerably less neurotoxicity than otherschedules. However, the high percentage of diarrhea suggests that a dosereduction of 5-FU in this regimen may result in better therapeutic synergy.
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  • 44
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 887-889 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; lung metastases ; spontaneous pneumothorax
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Pneumothorax occurring in the absence of obvious lungdisease is defined as spontaneous pneumothorax. Spontaneous pneumothoraxoccurs in a variety of settings in patients with malignancies. Patients and methods:We present a case report of spontaneouspneumothorax in malignancy and review the literature. Results:No correlation was found between the occurrence ofpneumothorax with age, sex or smoking history. Pneumothorax occurred with avariety of primary tumors. However it was always associated with lungmetastases or lung involvement with tumor. In certain cases the metastaseswere detected after the occurrence of pneumothorax. Conclusions:The occurrence of pneumothorax in a patient withmalignancy should prompt a search for lung metastases.
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  • 45
    ISSN: 1569-8041
    Schlagwort(e): adjuvant ; chemotherapy ; gastric cancer ; meta-analysis ; randomised clinical trial
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Several studies have investigated the possible roleof the adjuvant chemotherapy after curative resection for gastric cancerfailing to show a clear indication; previous meta-analyses suggested smallsurvival benefit of adjuvant chemotherapy, but the statistical methods usedwere open to criticisms. Materials and methods:Randomised trials were identified by meansof Medline and CancerLit and by selecting references from relevant articles.Systematic review of all randomised clinical trials of adjuvant chemotherapyfor gastric cancer compared with surgery alone, published before January 2000,were considered. Pooling of data was performed using the fixed effect model.Death for any cause was the study endpoint. The hazard ratio and its95% confidence intervals (95% CI), derived according to themethod of Parmar, were the statistics chosen for summarising the relativebenefit of chemotherapyversuscontrol. Results:Overall 20 articles (21 comparisons) were considered foranalysis. Three studies used single agent chemotherapy, seven combination of5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU withoutanthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82,95% CI: 0.75–0.89, P 〈 0.001). Association ofAnthracyclines to 5-FU did not show a statistically significant improvementwhen compared with the effect of the other regimens. Conclusions:Chemotherapy produces a small survival benefit inpatients with curatively resected gastric cancer. However, taking into accountthe limitations of literature based meta-analyses, adjuvant chemotherapy isstill to be considered as an investigational approach.
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  • 46
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 1343-1347 
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; Her2/neu ; indolent ; malignant ; palliative care ; secretory breast cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Secretory carcinoma of the breast is a rare and indolent tumour originallydescribed in children but occurring equally in the adult population. Theprincipal management problems following primary surgical treatment are localrecurrence and axillary lymph node metastases. Distant metastases areextremely rare. We present the case of a 27-year-old woman with pulmonary metastases froma secretory breast cancer treated by mastectomy and axillary lymph nodedissection 12 years previously. There was no response to chemotherapy; however, the patient remained aliveand active two years from presentation with metastatic disease and one yearfrom cessation of all cytotoxic chemotherapy. She eventually died ofrespiratory failure two and a half years after presentation. To our knowledge, this is only the fourth reported case of distantmetastases from secretory breast cancer and the second reported case in whichcurrent active chemotherapy has been used. We review the literature anddiscuss the apparent chemoresistance of this tumour including the lack ofmembrane staining for Her2/neu. In the absence of any proven effective chemotherapy we believe that symptomcontrol becomes the focus of management and offers patients with metastaticsecretory breast cancer the greatest chance of a functional and good qualityexistence.
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  • 47
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; drug interaction ; in vitroassay
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: Chemotherapy using multi-drug regimens is consideredmore active than single-agent therapy. This may be due to synergisticinteractions or, simply, a higher probability of administering an activeagent. We investigated in vitrothe type of drug interactions in arecognized regimen in relationship to tumour type and drug sensitivity. Patients and methods: The possibility of synergistic and additiveinteractions between individual cytotoxic drugs was investigated for thecomponent drugs of the established FEC regimen, i.e., 5-fluorouracil,epirubicin and cyclophosphamide, in 243 patient tumour samples representingvarious drug sensitivity using the non-clonogenic fluorometric microculturecytotoxicity assay. Results: Using a cell survival of ≤50% as a limit fordrug activity and sample sensitivity, the overall response rates to the mostactive single drug (Dmax) and the combination were 56% and64%, respectively, with a distribution among diagnoses similar to thatin the clinic. For 86% of the samples there was concordance withrespect to judgement of activity using either Dmax or thecombination. For samples being sensitive to at least one single drug,95% were also sensitive to the combination whereas for samples withinsignificant Dmax effect, only 2% were sensitive to thecombination. In samples with modest Dmax effects, i.e., cellsurvival in the range 〉50%–≤80%, 45%responded to the combination. The effect of the combination was generally wellpredicted from the Dmax effect. Conclusions:The superior antitumour effect of drug combinationscompared with single drugs may be due to the higher chance of selecting anactive agent. However, for intermediately sensitive tumours, additionalinteraction effects of a combination may be of clinical significance.
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  • 48
    ISSN: 1569-8041
    Schlagwort(e): carcinosarcoma ; chemotherapy ; thyroid
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Thyroid carcinosarcoma is a rare and aggressive thyroid tumor. Histologicalexamination of a tumor showed the characteristic of epithelial carcinoma andmesenchymal differentiation. We retrospectively analyzed the course of thepatient and reviewed the literature in which only 19 other cases aredescribed. Carcinosarcoma of the thyroid is a very aggressive tumor with aclinical course similar to anaplastic thyroid carcinoma. Survival is veryshort despite aggressive multimodal treatment.
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  • 49
    ISSN: 1569-8041
    Schlagwort(e): acute myeloid leukemia ; chemotherapy ; chronic lymphocytic leukemia ; immunosuppression ; second neoplasms
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract An increased incidence of different malignancies associated to chroniclymphocytic leukemia (CLL) has been reported. The association of CLL and acuteleukemia is a rare event described in 〈1% of CLL, the type of acuteleukemia being either from the lymphoid or more often from the myeloidlineage. The coexistence of acute myeloid leukemia (AML) and CLL in the samepatient has been occasionally reported. Most of these cases have beenassociated with the administration of chemotherapy or radioterapy for CLL,suggesting that the former may be a secondary leukemia. On the other hand, CLLcould precede, but could also be diagnosed at the same, or delayed time asAML, suggesting the presence of other leukemogenic factors. We describe theexceptional development of AML and lung cancer in a patient with previouslydiagnosed CLL in minimal residual disease status after fludarabine treatmentfollowed by autologous peripheral blood stem-cell transplantation.
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  • 50
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; interferon ; transitionall-cell carcinoma ; urothelial tract
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Based on the favorable results of the combination5-fluorouracil (5-FU), cisplatin and interferon-α as second-line treatmentin advanced metastatic transitional-cell carcinoma of the urothelial tract aconfirmatory study was executed in a multicenter setting. Patients and methods:In this open label phase II study 43patients failing adequate previous chemotherapy were treated with IFN-α2b5 MU/m2 subcutaneously for 5 consecutive days starting on day 1 and22 simultaneous with 5-FU 500 mg/m2 daily as a continuous infusion.In between the same dose of IFN-α2b was given 3 times weekly with CDDP 25mg/m2 on days 1, 8, 15 and 22. This cycle was repeated every sixweeks. Results:In 40 eligible patients 5 PR were seen (12.5%;95% confidence interval (95% CI):4.1%–26.8%). The major toxicity was hematological. Twotoxic deaths were seen due to gastro-intestinal hemorrhage. Conclusions:In view of these results this combination can not berecommended as second line treatment for metastatic transitional-cellcarcinoma of the urothelial tract.
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  • 51
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; docetaxel ; gemcitabine ; non-small-cell lung cancer ; phase I trials ; taxanes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Docetaxel and gemcitabine are active in a broad rangeof malignancies. The objective of this phase I trial was to determine themaximally tolerated doses of the combination of docetaxel and gemcitabine. Patients and methods:Patients with advanced cancer, WHOperformance status 0–2, who had received up to one prior chemotherapyregimen were treated with gemcitabine on days 1 and 8 and docetaxel on day 8repeated every 21 days. Prophylactic ciprofloxacin was commenced on day 11 ofeach cycle and continued until the neutrophil count reached 1.0 ×109/l. G-CSF was not administered. Dose levels studied weredocetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200 and 100/1200mg/m2. Results:Thirty-nine patients were entered and all were assessablefor toxicity. The highest administered dose level was 100 mg/m2docetaxel and 1200 mg/m2 gemcitabine with dose limiting toxicitiesof febrile neutropenia, grade 4 neutropenia ≥7 days, grade 4thrombocytopenia, grade 3 stomatitis and/or grade 3 fatigue in three out ofsix patients. Treatment was well tolerated (40 cycles) in the 10 patientstreated at the recommended dose level (85/1200) with only a single episode offebrile neutropenia and grade 3 or 4 non-hematologic toxicity was infrequent.There was no significant pulmonary toxicity. Responses were seen in a rangeof malignancies including non-small-cell lung cancer. Conclusions:The recommended dose level of 85 mg/m2docetaxel and 1200 mg/m2 gemcitabine has a favourable toxicityprofile and is suitable for further investigation in phase II trials. Thisnon-platinum containing regimen warrants further investigation as a potentialalternative to platinum containing regimens in non-small-cell lung cancer andother malignancies.
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  • 52
    ISSN: 1569-8041
    Schlagwort(e): cervical cancer ; chemotherapy ; phase I ; radiotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background.Cisplatin and paclitaxel are active in cervical cancerand both are able to potentiate the effects of radiotherapy. In this study weevaluated the maximum-tolerated dose (MTD) of paclitaxel in combination witha fixed dose of cisplatin when given weekly concurrently with pelvicradiotherapy to patients with carcinoma of the cervix uteri. Patients and methods:Eighteen patients with cervical cancer wereenrolled in this study. Cisplatin (30 mg/m2) and paclitaxel(starting dose 40 mg/m2; 5 mg/m2 escalation per level)were given on day 1 of radiotherapy and then weekly for six times.Radiotherapy was given to the pelvis with a four-field box technique for fivedays each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of threepatients were enrolled at each level and three further patients were includedif one or two dose-limiting severe adverse events (SAE) were recorded. SAE wasdefined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomitingand alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (〉1week) neutropenia or thrombocytopenia. Results:Four levels were studied (paclitaxel 40, 45, 50, 55mg/m2) with three, five, four and six patients enrolled,respectively. The MTD of paclitaxel was found at 50 mg/m2/wk andcisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity.Thirteen patients were evaluable for response: seven complete and five partialresponses were obtained with an overall response rate of 92.3%. Conclusions:The MTD of paclitaxel is 50 mg/m2/wk whenassociated to cisplatin 30 mg/m2/wk and concurrent pelvicradiotherapy. Diarrhea is the dose limiting side effect. Preliminary datasuggest that concurrent chemoradiotherapy with paclitaxel and cisplatin couldbe a very active treatment for patients with locally advanced carcinoma of thecervix.
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  • 53
    Digitale Medien
    Digitale Medien
    Springer
    Annals of oncology 11 (2000), S. 509-513 
    ISSN: 1569-8041
    Schlagwort(e): assessment ; chemotherapy ; eripheral neuropathy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 54
    ISSN: 1569-8041
    Schlagwort(e): advanced breast cancer ; chemotherapy ; gemcitabine ; vinorelbine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Gemcitabine and vinorelbine have shown activity inbreast cancer. A phase II trial was initiated in order to evaluate theresponse rate (RR) and time to progression (TTP) of the combination of the twodrugs in patients with metastatic breast cancer progressing after first-linetaxane-based chemotherapy. Patients and methods:Thirty-one patients were treated with thecombination of gemcitabine 1000 mg/m2 days 1 + 8 and vinorelbine30 mg/m2 days 1 + 8. The cycles were repeated every three weeks. Results:Of 27 evaluable patients 1 (4%, 95%confidence interval (95% CI): 0.1%–19%) achievedcomplete remission (CR), five (18%; 95% CI:6%–38%) partial remission (PR), eleven (40%;95% CI: 22%–61%) stable disease and ten patientsprogressed. The median duration of response was six months (range 4–10+)and the median duration of disease stabilization was five months (range2–22+). With a median follow-up of 16 months (range 0.4–22+) themedian TTP was 3.5 months (range 0.4–22+) and the median survival was9.5 months (range 0.4–22+). Grade 3–4 toxicities weregranulocytopenia 15 patients (48%), rash 3 patients (10%),neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%).In conclusion the combination of gemcitabine/vinorelbine in the dosesadministered in this group of patients had a response rate of 22% andneeds to be further evaluated in metastatic breast cancer.
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  • 55
    ISSN: 1569-8041
    Schlagwort(e): chemotherapy ; gemcitabine ; malignant glioma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose:We conducted a phase II multicentre study of gemcitabinein patients with anaplastic astrocytoma and glioblastoma multiforme at firstrelapse. Patients and methods:Patients with anaplastic astrocytoma orglioblastoma multiforme receiving a stable dose of steroids and ECOGperformance status ≤3 were eligible for this study at the time of firstrelapse. One adjuvant chemotherapy regimen was permissible. Patients receivedgemcitabine 1000 mg/m2 i.v. weekly × 3, repeated on afour-weekly cycle. Results:Of 20 patients enrolled, 15 were evaluable for response,19 for non-hematological toxicity and 18 for hematological toxicity. Sevenpatients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme(GBM). Age ranged from 28–71 years (median 50). Fifteen patientsdiscontinued therapy due to disease progression. The median number of cyclesadministered was 1 (range 1–11); only two patients received more thanthree cycles. Hematologic toxicity was acceptable and no grade 4 toxicity wasseen. One patient developed Pneumocystispneumonia and eventualpulmonary embolism; one died of gastric hemorrhage related to steroid therapy.No objective responses were seen. Nine patients had stable disease (medianduration 2.7 months, range 0.9–11.2). Conclusions:Gemcitabine given in this dose and schedule seemswell tolerated but is not active in patients with recurrent high-gradegliomas.
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  • 56
    Digitale Medien
    Digitale Medien
    Springer
    Journal of clinical immunology 20 (2000), S. 229-239 
    ISSN: 1573-2592
    Schlagwort(e): Aging ; apoptosis ; TNF receptor ; Fas ; Fas ligand ; mitochondria
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The cellular and molecular basis of immune senescence is unclear. A number of mechanisms have been proposed. In this issue of the Journal of Clinical Immunology, some of the mechanisms for various immunologic abnormalities in aging are presented. In this article, various molecular steps of both death receptor and mitochondrial pathways of apoptosis in general are reviewed. In particular, the role of apoptosis in T-cell immune senescence is discussed.
    Materialart: Digitale Medien
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  • 57
    Digitale Medien
    Digitale Medien
    Springer
    Reviews in endocrine & metabolic disorders 1 (2000), S. 225-231 
    ISSN: 1573-2606
    Schlagwort(e): thyroid neoplasms ; chemotherapy ; anaplastic carcinoma ; lymphoma ; therapeutics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
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  • 58
    ISSN: 1573-4919
    Schlagwort(e): tumour necrosis factor ; receptors ; subtypes ; calcium ; apoptosis ; cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract Tumour necrosis factor-α (TNF) receptors mediate a variety of effects dependent on cell type. A role for Ca2+ in TNF-induced death remains uncertain. Here we investigated restricting intracellular/extracellular Ca2+ in HeLa epithelial carcinoma cells expressing low and high levels of p75TNFR receptor subtype and KYM-1 rhabdomyosarcoma cells, models of rapid TNF-induced apoptosis. Ca2+-chelators EGTA and BAPTA-AM as well as microsomal Ca2+-ATPase inhibitor thapsigargin, did not alter TNF-induced death. TNF was also unable to alter resting [Ca2+]i levels which remained 〈 200 nM even during times when these cells were undergoing apoptotic cell death. These findings indicate no role for modulated Ca2+ concentrations in TNF-induced apoptotic cell death.
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  • 59
    ISSN: 1573-4919
    Schlagwort(e): phosphatidylserine ; base exchange ; apoptosis ; thymocytes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract The exposure of phosphatidylserine toward the external surface of the membrane is a well-established event of programmed cell death. The possibility that an apoptotic stimulus influences the metabolism of this phospholipid could be relevant not only in relation to the previously mentioned event but also in relation to the capability of membrane phosphatidylserine to influence PKC activity. The present investigation demonstrates that treatment of mouse thymocytes with the apoptotic stimulus dexamethasone, enhances the incorporation of [3H]serine into phosphatidylserine. Cell treatment with dexamethasone also enhanced the activity of serine base exchange enzyme, assayed in thymocyte lysate. Both the effects were observed at periods of treatment preceding DNA fragmentation. The addition of unlabelled ethanolamine, together with [3H]serine to the medium containing dexamethasone-treated thymocytes lowered the radioactivity into phosphatidylserine. Serine base exchange enzyme activity was influenced by the procedure used to prepare thymocyte lysate and was lowered by the addition of fluoroaluminate, that is widely used as a G-protein activator. The increase of serine base exchange enzyme activity induced by dexamethasone treatment was observed independently by the procedure used to prepare cell lysate and by the presence or absence of fluoroaluminate.
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  • 60
    Digitale Medien
    Digitale Medien
    Springer
    Molecular and cellular biochemistry 212 (2000), S. 35-43 
    ISSN: 1573-4919
    Schlagwort(e): cAMP ; CRE ; Cox-2 ; NO ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract Previous studies revealed that expression and activation of cyclooxygenase-2 (Cox-2) conveyed a protective principle in murine macrophages, thus attenuating pro-apoptotic actions of chemotherapeutic agents or programmed cell death as a result of massive nitric oxide (NO) generation. Expression of Cox-2 was achieved by treatment of cells with lipopolysaccharide/interferon-γ or nontoxic doses of NO releasing agents. We reasoned E-type prostanoid formation, and in turn an intracellular cAMP increase as the underlying protective mechanism. To prove our hypothesis, we analyzed the effects of lipophilic cAMP-analogs on NO, cisplatin, or etoposide induced apoptosis in RAW 264.7 macrophages. Selected apoptotic parameters comprised DNA fragmentation (diphenylamine assay), annexin V staining of phosphatidylserine, caspase activity (quantitated by the cleavage of a fluorogenic caspase-3-like substrate Ac-DEVD-AMC), and mitochondrial membrane depolarisation (ΔΨ). Western blots detected accumulation of the tumor suppressor protein p53, relocation of cytochrome c to the cytosol, and expression of the anti-apoptotic protein Bcl-xL. Prestimulation with lipophilic cAMP-analogs attenuated apoptosis with the notion that cell death parameters were basically absent. To verify gene induction by cAMP in association with protection we established activation of cAMP response element binding protein (CREB) by gel-shift analysis and moreover, treated macrophages with oligonucleotides containing a cAMP-responsive element (CRE) in order to scavenge CREB. Decoy oligonucleotides, but not control oligonucleotides, attenuated cAMP-evoked protection and reestablished pro-apoptotic parameters. We conclude that gene induction by cAMP protects macrophages towards apoptosis that occurs as a result of excessive NO formation or addition of chemotherapeutica. Attenuating programmed cell death by the cAMP-signaling system may be found in association with Cox-2 expression and tumor formation.
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  • 61
    ISSN: 1573-4919
    Schlagwort(e): T-type Ca2+ channel ; polyglutamine-expanded androgen receptor ; CAG trinucleotide repeats ; spinobulbar muscular atrophy ; apoptosis ; motorneuron ; cell lines ; neuroblastoma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (ω-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
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  • 62
    Digitale Medien
    Digitale Medien
    Springer
    Molecular and cellular biochemistry 203 (2000), S. 59-71 
    ISSN: 1573-4919
    Schlagwort(e): PTEN tumor suppressor ; cyclin-dependent kinase inhibitors ; apoptosis ; chemosensitivity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract The recently discovered tumor suppressor gene PTEN has been found mutated in many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulatory controls to achieve this growth-inhibitory effect. We found that overexpression of PTEN stimulates the synthesis of three inhibitors of cyclin-dependent kinases, p21WAF1, p27KIP1, and p57,KIP2. This effect is very specific, as the expression of other components of the cell cycle engine, various cyclins and cyclin-dependent kinases, is not affected. For p21WAF1 we show that this induction is due to the p53-independent transcriptional activation of its promoter. In addition, increased expression of PTEN rendered the cells more sensitive to apoptotic cell death. Therefore, our data suggest a two-fold mechanism of growth inhibition by PTEN: one that acts via the increased expression of CKIs such as p21WAF1, and another that augments the cellular propensity for apoptotic cell death.
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  • 63
    ISSN: 1573-4919
    Schlagwort(e): retinoic acid ; RARβ ; protein kinase A ; apoptosis ; caspase
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract Both cAMP and retinoids play a role in cell differentiation and the control of cell growth. A site-selective cAMP analog, 8-Cl-cAMP and retinoic acid synergistically inhibit growth and induce apoptosis in certain cancer cells. In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective even at doses that are toxic to the host. The objective of our present study was to examine the mechanism(s) of synergistic effects of retinoic acid (9-cis, 13-cis or all-trans RA) and 8-Cl-cAMP on apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. RA induced growth inhibition and apoptosis in OVCAR-3 and OVCAR-8 cells. 8-Cl-cAMP acted synergistically with RA in inducing and activating retinoic acid receptor β (RARβ) which correlates with growth inhibition and apoptosis in both cell types. In addition, induction of apoptosis by RA plus 8-Cl-cAMP requires caspase-3 activation followed by cleavage of anti-poly(ADP-ribose) polymerase. Furthermore, mutations in CRE-related motif within the RARβ promoter resulted in loss of both transcriptional activation of RARβ and synergy between RA and 8-Cl-cAMP. RARβ expression appears to be associated with induction of apoptosis. Introduction of the RARβ gene into OVCAR-3 cells resulted in gain of RA sensitivity. Loss of RARβ expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. Thus, combined treatment with RA and 8-Cl-cAMP may provide an effective means for inducing RARβ expression leading to apoptosis in ovarian cancer cells.
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  • 64
    Digitale Medien
    Digitale Medien
    Springer
    Molecular and cellular biochemistry 204 (2000), S. 83-88 
    ISSN: 1573-4919
    Schlagwort(e): FHIT ; cell cycle ; ecdysone ; tumor suppressor ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract The mechanism of tumor suppressor action of the fragile histidine triad (FHIT) gene is unknown. Disruption of cell cycle regulation leads to the tumor formation and many tumor suppressor genes suppress tumorigenesis through their effect on cell cycle regulation. We examined the expression of FHIT during the cell cycle, and determined whether overexpression of FHIT affects cell cycle kinetics and apoptosis. The FHIT cDNA was cloned into the ecdysone-inducible expression vector in both the sense and antisense orientations. Overexpression of the sense or antisense construct did not affect cell proliferation, cell cycle distribution or apoptosis in human 293T cells. Analysis of the FHIT expression in 293T cells collected at various cell cycle phases showed that the expression of FHIT is not under cell cycle regulation. These results indicate that the tumor suppressor activity of the FHIT gene may be independent of an effect on the cell cycle and apoptosis mechanisms.
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  • 65
    Digitale Medien
    Digitale Medien
    Springer
    Molecular and cellular biochemistry 207 (2000), S. 19-27 
    ISSN: 1573-4919
    Schlagwort(e): PKC ; apoptosis ; bile acid ; hepatocyte
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract The effect of GCDC-induced apoptosis on PKC activity and PKC's role in GCDC-induced hepatocyte apoptosis is unclear. The specific aims of this study were to determine if GCDC-induced apoptosis changed intracellular PKC activity and if modulation of PKC activity affected GCDC-induced hepatocyte apoptosis. Apoptosis was induced in isolated hepatocytes using GCDC. PKC activity was measured and specific PKC and calpain inhibitors were used to study the effects of PKC and calpain modulation on GCDC-induced apoptosis. After 4 h exposure, 50 μM GCDC induced apoptosis in 42% of hepatocytes. Intracellular PKC activity decreased to 44% of controls 2 h after exposure of hepatocytes to GCDC (p 〈 0.001). Pre-incubation of hepatocytes with the calpain protease inhibitor restored PKC activity in GCDC exposed hepatocytes to 91± 5% of control cells. Pre-incubation of hepatocytes with a calpain inhibitor decreased GCDC-induced apoptosis as did pre-incubation with the PKC activating phorbol ester, PMA. The combination of calpain inhibition and PMA further reduced GCDC-induced apoptosis but caused low level hepatic apoptosis. Inhibition of PKC with chelerythrine also substantially reduced GCDC-induced hepatocyte apoptosis. GCDC-induced apoptosis is associated with decreases in total cellular PKC activity, which appear to be dependent on intracellular calpain-like protease activity. The combination of protease inhibition and phorbol ester pretreatment preserved total cellular PKC activity and decreased GCDC-induced apoptosis but induced low level apoptosis in the absence of GCDC exposure. PKC inhibition also decreased GCDC-induced hepatocyte apoptosis highlighting the complex interactions of PKC and proteases during GCDC-induced apoptosis.
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  • 66
    Digitale Medien
    Digitale Medien
    Springer
    Molecular and cellular biochemistry 212 (2000), S. 19-28 
    ISSN: 1573-4919
    Schlagwort(e): melanoma ; transcription factors ; CREB ; invasion ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract The purpose of this study was to determine the role of CREB and its associated proteins in melanoma progression. We used MeWo human melanoma cells transfected with a dominant negative construct of CREB, KCREB. KCREB has a mutation in its DNA-binding domain and can not bind the CRE element. Expression of KCREB yields proper heterodimerization with CREB and its associated proteins, but the proteins associated with KCREB do not confer the same degree of transcriptional activity as they would in the case of wild-type CREB. Here, we demonstrate that expression of KCREB in MeWo melanoma cells leads to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain at least partially this effect of KCREB. The first, is one in which CREB and its associated proteins play an essential role in invasion. We showed that the invasive properties of KCREB-transfected MeWo cells were reduced due to the downregulation of the CRE-dependent expression of the type IV collagenase MMP-2 and the adhesion molecule MCAM/MUC18. In the second mechanism, CREB and its associated proteins act as survival factors for human melanoma cells. Here we demonstrated that expression of KCREB in MeWo cells rendered them susceptible to apoptosis induced by thapsigargin, which in turn increased the intracellular level of Ca2+. Thapsigargin induced CREB and ATF-1 phosphorylation and activated CRE-dependent transcription in MeWo cells. Collectively, our data demonstrate that CREB and its associated proteins play an important role in tumor growth and metastasis of human melanoma.
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  • 67
    ISSN: 1573-689X
    Schlagwort(e): bedside wellness system ; chemotherapy ; fatigue ; emesis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background: The bedside wellness system (BSW) is effective for decreasing stress and improving mental well-being and should help relieve the side effects and mental disorders of patients during cancer chemotherapy. Methods: The study was a randomized clinical trial. After giving informed consent, patients were randomly assigned to the BSW intervention or control groups. The patients were given the Hospital Anxiety and Depression Scale (HADS) test before the trial to evaluate their emotional baseline. The Cancer Fatigue Scale, which was developed at our institute, and face visual analog scale were used to measure the emotional state and subjective feelings before and after the trial. The degree of emesis was measured using a visual analogue scale after the experience. We set up the system in a room in the outpatient clinic of the National Cancer Center New Hospital Building. Results: The decreases in the fatigue score and emesis score 3–5 days after chemotherapy were statistically significant (both p 〈 0.05) and carry-over effects were detected. Conclusions: BSW intervention therapy is an effective way to treat fatigue and emesis. This virtual reality system is a new therapeutic method that can be used in palliative medicine.
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  • 68
    Digitale Medien
    Digitale Medien
    Springer
    Cancer and metastasis reviews 19 (2000), S. 87-92 
    ISSN: 1573-7233
    Schlagwort(e): angiogenesis ; endothelial cell survival ; apoptosis ; thrombospondin-1
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Angiogenesis is a process of capillary formation from pre-existing blood vessels. It is tightly controlled by the balance between positive and negative environmental signals – inducers and inhibitors of angiogenesis in such a way that predominance of inducers results in angiogenesis and predominance of inhibitors – in vascular quiescence. Here we discuss the ability of the angiogenic stimuli to promote survival and the pathways they may utilize. We also summarize information available on the signaling events elicited in the endothelial cells by a naturally occurring inhibitor of angiogenesis Thrombospondin-1 (TSP-1), that result in the endothelial cell apoptosis and inhibition of angiogenesis in vivo. This ability to cause programmed cell death in vascular endothelium is not unique to TSP-1. A substantial number of known angiogenesis inhibitors can also trigger apoptosis in the activated endothelial cells. This fact argues for the possibility of apoptosis to be a common denominator for a major fraction of anti-angiogenic molecules. If this is the case, it is equally possible that the ratio between environmental factors that control angiogenesis is interpreted within individual endothelial cell as a balance between pro-apoptotic and survival signals. Thus the relative strength of the death and survival signal or signals determines the fate of endothelial cell and therefore the fate of remodeling vessel.
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  • 69
    ISSN: 1573-7039
    Schlagwort(e): estrous cycle ; mammary gland ; rat ; proliferation ; differentiation ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The Sprague-Dawley rat is highly regarded for studies designed to investigate the effects of endocrine modulation on mammary carcinogenesis. In this study, we further evaluate the validity of the Sprague-Dawley rat model for the study of human breast cancer by evaluating the effects of normal 4-day estrous cycling on mammary epithelial cell proliferation, differentiation, and apoptotic death. Trends in mammary gland development with stage of 4-day estrous cycle were evident. Mammary glands isolated from follicular and early luteal stages had predominantly ductal histoarchitecture, whereas glands isolated from mid-late luteal were predominantly lobuloalveolar. Quantitation of BrdU incorporation revealed that epithelial cell proliferation was eight-fold higher in metestrus and diestrus-1 than in proestrus. Expression of β-casein and whey acidic protein (WAP)4 mRNA was also highly dependent on stage of estrous, with detection restricted to midcycle. Apoptotic cell death of mammary epithelium was found to be suppressed during the peak in cell proliferation. TRPM-2/clusterin mRNA was elevated when apoptosis was low and milk protein mRNA levels were high, consistent with putative roles for TRPM-2/clusterin in inhibiting cell death in regressing tissues and inducing mammary epithelial cell differentiation. Cell proliferation, differentiation, and death occurred only in a subset of epithelial cells per estrous cycle, and these cells appeared randomly distributed throughout multiple ductules and alveoli. These observations suggest that cellular response(s) to ovarian hormone-dependent signals is asynchronous. Cumulatively, these observations demonstrate that rat mammary epithelial cell proliferation, differentiation, and death are under the control of cycling ovarian hormones, similarly to the human mammary epithelium during the menstrual cycle.
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  • 70
    ISSN: 1573-7276
    Schlagwort(e): apoptosis ; butyrate ; cell cycle ; cholesteryl butyrate ; drug delivery ; melanoma ; solid lipid nanospheres
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G0/1-S transition block and a `sub-G0/1' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.
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  • 71
    Digitale Medien
    Digitale Medien
    Springer
    Journal of assisted reproduction and genetics 17 (2000), S. 168-173 
    ISSN: 1573-7330
    Schlagwort(e): Aging ; apoptosis ; granulosa cells ; in vitro fertilization ; oocyte quality
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: The objective was to determine the effects of women'sage on the ovarian fecundity as assessed by the incidenceof apoptotic granulosa cells. Methods: Twenty-eight normo-ovulatory women underwentovulation induction for standard IVF. The husbands of thesewomen showed severe male infertility factors. The womenwere divided into four groups according to their ages. Womenunderwent follicle aspiration after the administration ofhuman menopausal gonadotropin plus human chorionicgonadotropin. The nuclei of granulosa cells were examinedby using fluorescence microscopy, and the incidence of apoptotic granulosa cells was tabulated. Results: Granulosa cells in the older women revealed asignificant increase in the number of apoptotic cells. Thenumber of total oocytes and the number of mature oocytesobtained significantly decreased with age. However, endometrial thickness and follicular estradiol, progesterone, andfree testosterone levels were not significantly different amongfour different age groups. Conclusions: Age increases apoptotic changes in granulosacells and consequently decreases the ovarian fecundity.
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  • 72
    Digitale Medien
    Digitale Medien
    Springer
    Journal of bioenergetics and biomembranes 32 (2000), S. 15-25 
    ISSN: 1573-6881
    Schlagwort(e): Mitochondria ; endoplasmic reticulum ; Ca2+ ; IP3 ; local signaling ; energy metabolism ; apoptosis ; necrosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Physik
    Notizen: Abstract Many agonists bring about their effects on cellular functions through a rise incytosolic [Ca2+]([Ca2+]c) mediated by the second messenger inositol 1,4,5-trisphosphate (IP3). Imaging studiesof single cells have demonstrated that [Ca2+]c signals display cell specific spatiotemporalorganization that is established by coordinated activation of IP3 receptor Ca2+ channels.Evidence emerges that cytosolic calcium signals elicited by activation of the IP3 receptors areefficiently transmitted to the mitochondria. An important function of mitochondrial calciumsignals is to activate the Ca2+-sensitive mitochondrial dehydrogenases, and thereby to meetdemands for increased energy in stimulated cells. Activation of the permeability transitionpore (PTP) by mitochondrial calcium signals may also be involved in the control of cell death.Furthermore, mitochondrial Ca2+ transport appears to modulate the spatiotemporal organizationof [Ca2+]c responses evoked by IP3 and so mitochondria may be important in cytosolic calciumsignaling as well. This paper summarizes recent research to elucidate the mechanisms andsignificance of IP3-dependent mitochondrial calcium signaling.
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  • 73
    Digitale Medien
    Digitale Medien
    Springer
    Journal of bioenergetics and biomembranes 32 (2000), S. 35-46 
    ISSN: 1573-6881
    Schlagwort(e): Ca2+ signaling ; inositol 1,4,5-trisphosphate receptor ; mitochondrial Ca2+ uptake ; mitochondrial Ca2+ efflux ; permeability transition ; apoptosis ; Bcl-2 family
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Physik
    Notizen: Abstract Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injuryand programmed cell death; mitochondria play a pivotal role in the regulation of such cytosolicCa2+ ([Ca2+]c) signals. Mitochondria are endowed with multiple Ca2+ transport mechanismsby which they take up and release Ca2+ across their inner membrane. These transport processesfunction to regulate local and global [Ca2+]c, thereby regulating a number of Ca2+-sensitivecellular mechanisms. The permeability transition pore (PTP) forms the major Ca2+ effluxpathway from mitochondria. In addition, Ca2+ efflux from the mitochondrial matrix occursby the reversal of the uniporter and through the inner membrane Na+/Ca2+ exchanger. Duringcellular Ca2+ overload, mitochondria take up [Ca2+]c, which, in turn, induces opening of PTP,disruption of mitochondrial membrane potential (ΔΨm) and cell death. In apoptosis signaling,collapse of ΔΨ;m and cytochrome c release from mitochondria occur followed by activationof caspases, DNA fragmentation, and cell death. Translocation of Bax, an apoptotic signalingprotein from the cytosol to the mitochondrial membrane, is another step during thisapoptosis-signaling pathway. The role of permeability transition in the context of cell death in relationto Bcl-2 family of proteins is discussed.
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  • 74
    Digitale Medien
    Digitale Medien
    Springer
    Neurochemical research 25 (2000), S. 71-76 
    ISSN: 1573-6903
    Schlagwort(e): Arginylation ; post-translational modification ; apoptosis ; PC12 cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The aim of this study was to analyze the N-terminal post-translational incorporation of arginine into cytosolic proteins from cultured cells and the in vitro incorporation of arginine into soluble proteins of PC12 cells after serum deprivation. Arginine incorporation was measured in the presence of protein synthesis inhibitors. None of the inhibitors used affected significantly the arginylation reaction while the novo synthesis of protein was reduced by 98%. Under these conditions, we found that of the total [14C]arginine incorporated into the proteins, around 20% to 40% was incorporated into the N-terminal position of soluble proteins by a post-translational mechanism. These results suggest that this post-translational aminoacylation may be a widespread reaction in neuronal and non-neuronal cells. We also found that in PC12 cells, the in vitro post-translational arginylation was 60% higher in apoptotic cells with respect to control cells. These findings suggest that the post-translational arginylation of proteins may be involved in programmed cell death.
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  • 75
    Digitale Medien
    Digitale Medien
    Springer
    Neurochemical research 25 (2000), S. 341-347 
    ISSN: 1573-6903
    Schlagwort(e): Neuronal survival ; apoptosis ; Heat-Shock Proteins ; HSP-70 ; NMDA
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Cerebellar granule cells (CGC) die apoptotically after five days in culture (DIV) at physiological concentrations of potassium (5 mM; K5). When CGC are depolarized (K25) or treated with NMDA (150 μM) cell survival is increased. CGC changed from K25 to K5 die after 24–48 h. It is known that heat shock protein (HSP) may protect from cell death. Here, we found that cells in K5 showed an increase in HSP-70 levels after 3 DIV. Similarly, in cells changed from K25 to K5, HSP-70 levels were increased after 6 h. Neither NMDA nor K25 treatment affected HSP-70 levels from 2–7 DIV. Ethanol or thermal stress induced HSP-70, but cell survival was not affected in K5 medium. These results suggest that HSP, particularly HSP-70, are not involved in the mechanisms by which NMDA and KCl promote cell survival.
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  • 76
    ISSN: 1573-7217
    Schlagwort(e): cerbB2 ; chemotherapy ; neoadjuvant ; prognosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Recent advances in the detection and treatment of breast cancer have led to an intensive search for new markers of both prognosis and chemoresponsiveness. The oncogene cerbB2 has proved to be one of the most promising markers currently under study, both as a predictor of chemoresponsiveness and as a marker of poor prognosis. In addition the increasing use of neoadjuvant chemotherapy has led to the loss of standard prognostic criteria. In order to study the potential role of cerbB2 expression as an indicator of chemoendocrine resistance and poor prognosis, both before and after chemotherapy, we obtained tumour sections from 283 women enrolled onto a neoadjuvant trial. In this trial patients were randomised to receive either primary surgery followed by adjuvant chemoendocrine treatment or neoadjuvant chemoendocrine therapy followed by surgery. CerbB2 status was determined immunohistochemically on all of these patients. Thirty-eight percent of the tumours were cerbB2 positive. There was no significant difference in expression between the adjuvant (41%) and neoadjuvant arms (35%). CerbB2 positive patients were much more likely to have shown non-response to chemoendocrine therapy (p〈0.001) and had a worse DES (p〈0.05). The best prognosis was seen in cerbB2 negative patients receiving neoadjuvant chemoendocrine therapy who showed a significantly better DFS (p〈0.05), than the cerbB2 negative patients receiving adjuvant therapy.
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  • 77
    Digitale Medien
    Digitale Medien
    Springer
    Breast cancer research and treatment 62 (2000), S. 223-235 
    ISSN: 1573-7217
    Schlagwort(e): adriamycin ; apoptosis ; DNA damage ; growth arrest ; ionizing radiation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of animmediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
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  • 78
    ISSN: 1573-7217
    Schlagwort(e): adriamycin ; apoptosis ; breast tumor cells ; EB 1089 ; vitamin D
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Exposure of MCF-7 breast tumor cells to the vitamin D3 analog, EB 1089 enhances the response to adriamycin. Clonogenic survival studies indicate that EB 1089 shifts the dose-response curve for sensitivity to adriamycin by approximately six-fold in p53 wild-type MCF-7 cells; comparative studies in MCF-7 cells with a temperature-sensitive dominant negative p53 mutation show less than a two-fold shift in adriamycin sensitivity in the presence of EB 1089. The combination of EB 1089 with adriamycin also promotes apoptotic cell death in the p53 wild-type MCF-7 cells but not in the MCF-7 cells expressing mutant p53. EB 1089 treatment blocks the increase in p21waf1/cip1 levels induced by adriamycin and interferes with induction of MAP kinase activity by ionizing radiation, effects which could be related to the capacity of EB 1089 to promote secretion of insulin-like growth factor binding protein. Taken together with our previous findings that EB 1089 enhances breast tumor cell sensitivity to ionizing radiation, there studies further support the concept that vitamin D3 analogs could have utility in combination with conventional chemotherapy and/or radiotherapy in the treatment of breast cancer.
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  • 79
    Digitale Medien
    Digitale Medien
    Springer
    Breast cancer research and treatment 61 (2000), S. 183-195 
    ISSN: 1573-7217
    Schlagwort(e): breast cancer ; chemotherapy ; cohort study ; radiotherapy ; second primary cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Objectives and methods.The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. Results.Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR = 1.4, 95% CI (1.2–1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p = 0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR = 13.0, 95% CI: 6.8–22.3), followed by leukaemia (SIR = 3.1, 95% CI: 1.7–5.0), melanoma (SIR  =  2.7, 95% CI: 1.4–4.8), kidney (SIR = 2.5, 95% CI: 1.2–4.5), ovary (SIR = 2.0, 95% CI: 1.2–3.1) and uterine tumours (SIR = 1.9, 95% CI: 1.4–2.5). The SIR was 3.0 (95% CI 1.8–4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI : 1.4 – 2.4) in those aged 40–49 and 1.2 (95% CI 1.0–1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1–2.3) fold higher than in those who had not received radiotherapy as initial treatment. Conclusion.In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.
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  • 80
    ISSN: 1573-7217
    Schlagwort(e): apoptosis ; breast cancer ; melatonin ; retinoic acid
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract It has been established that melatonin (Mlt) and retinoic acid, individually, inhibit the proliferation of the estrogen receptor-alpha (ERα)-positive MCF-7 breast cancer cell line. Our laboratory has previously demonstrated that Mlt and all-trans-retinoic acid (atRA) not only inhibit the proliferation, but also induce apoptosis of MCF-7 cells when used in a sequential regimen of Mlt followed 24 h later by atRA. Using this same MCF-7 breast cancer cell line, we investigated the potential pathways through which apoptosis is being induced. We found that treatment of MCF-7 cells with Mlt for 24 h before the addition of atRA decreased the protein levels of the death suppressor, Bcl-2, and increased, although with different time courses, the levels of the death promoters, Bax and Bak; however, there was no change in the levels of the tumor suppressor gene, p53. MCF-7 cells treated sequentially with Mlt and atRA also demonstrated an enhanced sensitivity to the apoptotic effects of atRA, which did not appear to be due to increased expression of the retinoic acid receptors, RARα or RXRα, but rather to enhanced transcriptional activity of the RARα. These data suggest that the sequential treatment regimen of Mlt and atRA may induce apoptosis by modulation of members of the Bcl-2 family of proteins. Thus, this combinatorial regimen, which reduces the concentration of atRA needed for clinical efficacy while enhancing its anti-tumorigenic activity, could be of great therapeutic benefit, and may, in fact, specifically induce the regression of established breast tumors due to its apoptosis-promoting effects.
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  • 81
    ISSN: 1573-7217
    Schlagwort(e): breast cancer ; locally advanced ; neoadjuvant ; chemotherapy ; paclitaxel ; cisplatin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background.In an earlier study, we have demonstrated a high response rate in metastatic breast cancer using paclitaxel (P) and cisplatin (C). A phase II study using the same regimen (PC) has been conducted in locally advanced breast cancer (LABC). Methods.A total of 72 consecutive patients with non-inflammatory LABC (T2 ≥ 4 cm, T3 or T4, N0–N2, M0). Patients were scheduled to receive 3–4 cycles of the neoadjuvant PC (paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 on day 1) every 21 days. Patients were then subjected to surgery and subsequently received 6 cycles of FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) or 4 cycles of AC (doxorubicin 60 mg/m2, and cyclophosphamide 600 mg/m2). Patients then received radiation therapy, and those with hormone receptor positive tumors were given adjuvant tamoxifen intended for 5 years. Results.The median age was 39 years (range, 24–78). Clinically, 7%, 58%, and 35% of patients had T2 ≥ 4 cm, T3, and T4, respectively. Disease stage at diagnosis was IIB (33%), IIIA (27%), and IIIB (40%). Complete and partial clinical response to PC was demonstrated in 13 (18%), and 52 (72%) patients, respectively. Of those patients with evaluable pathologic response (68 patients), complete pathologic response (pCR) was achieved in 15 (22%) patients. At a median follow-up of 22 (± 3.5) months, 58 (81%) were alive with no recurrence, nine (12%) were alive with evidence of disease, and five (7%) were dead. None of the patients achieving pCR has developed any relapse. The median overall survival has not been reached for all 72 patients with a projected 3-year survival (± SE) of 90% (± 4%). The median progression-free survival (PFS) was 42.1 (± 4.8) months with a projected PFS of 74% ± 7% at 3-years (for 68 patients). Conclusions.PC regimen in LABC produced a high pCR. The contribution of the other added modalities to survival could not be assessed.
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  • 82
    ISSN: 1573-7217
    Schlagwort(e): antisense oligodeoxynucleotides ; antineoplastic agents ; apoptosis ; Bcl-2 ; breast cancer ; chemosensitization
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract We have investigated the effects of transient Bcl-2 down-regulation induced by the Bcl-2 antisense oligodeoxynucleotide (ODN) G3139 (Genta Incorporated) in high Bcl-2 protein expressing, estrogen receptor (ER) positive MCF-7 and low Bcl-2 expressing, ER negative MDA435/LCC6 human breast cancer cells. Treatment with Bcl-2 antisense ODN in vitro caused 〉 80% reduction of Bcl-2 protein levels in a sequence specific manner for both cell lines. Maximum mRNA reduction was achieved within 24 h of the first antisense ODN exposure whereas full protein down-regulation required antisense exposure over 48 h. This Bcl-2 reduction was associated with 80–95% loss of viable cells compared to untreated cells. Similar cytotoxic effects were observed in both cell lines despite a nine-fold intrinsic difference in Bcl-2 protein expression suggesting that the relative degree of down-regulation of Bcl-2 is more important than the absolute reduction. Cell death associated with G3139 exposure exhibited properties indicative of apoptosis such as mitochondrial membrane depolarization and caspase activation. Combined treatment with G3139 and cytotoxic agents resulted in additive cytotoxicity in both cell lines. However, under most conditions studied, the direct cytotoxic activity of G3139 antisense was not synergistic with the cytotoxic agents. These results suggest that while Bcl-2 clearly constitutes an attractive therapeutic target due to its role in regulating apoptosis in breast cancer cells, additional mechanisms are important in the control of apoptosis arising from exposure to anticancer agents in vitro.
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  • 83
    ISSN: 1573-7217
    Schlagwort(e): adjuvant treatment ; breast cancer ; chemotherapy ; immunotherapy ; radiotherapy ; randomized trial
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract With a median follow-up of 14 years, the combination of polyadenylic–polyuridylic acid plus locoregional radiotherapy (257 patients) has significantly improved disease-free survival (p = 0.03) and significantly reduced the incidence of metastases (p = 0.04) when compared to CMF alone (260 patients), in women with operable breast cancer. The trial does not, however, permit an appreciation of the respective role of radiotherapy and PolyAU in these results.
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  • 84
    ISSN: 1573-7217
    Schlagwort(e): apoptosis ; breast cancer ; caspases ; NF-κB ; TRAIL
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Most breast cancer cell lines are resistant to TNF-related apoptosis inducing ligand (TRAIL) induced apoptosis. In sensitive breast cancer cell lines TRAIL rapidly induces the cleavage and activation of caspases leading to the subsequent cleavage of downstream caspase substrates. In contrast, there is no caspase activation in the resistant cell lines. The transcription factor NF-κB can inhibit apoptosis induced by a variety of stimuli including activation of death receptors. We investigated whether NF-κB contributes to the resistance of breast cancer cells to TRAIL induced apoptosis. All of the resistant breast cancer cell lines expressed NF-κB and had detectable NF-κB activity in nuclear extracts prior to treatment with TRAIL. Upon TRAIL treatment, a significant increase in NF-κB activity was seen in most of the cell lines. To directly test if NF-κB activity contributes to the resistance of these cell lines to TRAIL, we transiently transfected the resistant cell lines with an inhibitor of NF-κB (IκBΔN) and measured TRAIL induced apoptosis in control and transfected cells. All of the resistant cell lines tested showed an increase in TRAIL induced apoptosis when transfected with the IκBΔN. These results demonstrate that TRAIL resistant breast cancer cells fail to rapidly activate the apoptotic machinery but they do activate NF-κB. Inhibition of NF-κB activity increases the sensitivity to TRAIL mediated apoptosis in resistant cells. These results suggest that agents which inhibit NF-κB should increase the clinical efficacy of TRAIL in breast cancer cells.
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  • 85
    ISSN: 1573-7225
    Schlagwort(e): breast neoplasms ; chemotherapy ; female ; hormonal therapy ; invasive carcinoma ; multiple primary neoplasms ; radiation therapy ; thyroid neoplasms
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Background:Breast and thyroid cancer have been observed to occur more frequently than expected as multiple primary tumors in women. The study presented herein focuses on the effects of age at diagnosis and treatment for the first cancer on the development of the second cancer. Methods:This retrospective cohort study used a study population consisting of 38,632 women diagnosed with primary invasive breast cancer and 2189 women diagnosed with primary invasive thyroid cancer between 1974 and 1994. Cases were identified from records of the Cancer Surveillance System of western Washington and followed for subsequent cancer development through 1995. Results:Seventy-one women were diagnosed during their lives with both breast and thyroid cancers. Including cancers diagnosed during the same month as or after the initial cancer, the relative risk (RR) of breast cancer among women with thyroid cancer was 1.5 (95% confidence interval [CI] 1.1–2.0), and the RR of thyroid cancer among women with breast cancer was 1.5 (95% CI 1.1–2.2). Among women with thyroid cancer, risk of breast cancer was greatest when the latter cancer was diagnosed under 45 years of age (RR = 2.3, 95% CI 1.1–4.4). First course of treatment, including radiation or hormonal therapy to treat thyroid cancer, and radiation, chemotherapy, or hormonal therapy to treat breast cancer, did not alter a woman's risk of developing the second cancer. Conclusions:The data suggest that the incidence of breast and thyroid cancer may be related, and that in particular women with thyroid cancer may be at a moderately increased risk of developing breast cancer before age 45.
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  • 86
    ISSN: 1573-7217
    Schlagwort(e): apoptosis ; breast cancer ; continuous variables statistical analysis ; cytokeratins ; multiple correspondence analysis ; prognosis ; tissue cytosol ; tissue polypeptide antigen (TPA)
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Apoptosis is associated with caspase-mediated proteolysis of Type I (K18 and K19) cytokeratins. We previously showed a positive association between the levels of tissue polypeptide antigen (TPA), that recognizes cytokeratins K8, K18, and K19 fragments, and induced apoptosis in breast cancer cell lines. The aim of the present study was to evaluate the interrelationships between TPA, steroid receptors, and p53, and their joint prognostic role in node-negative breast cancer patients not treated with adjuvant therapies. Age and pT were also considered since they are known prognostic factors. Five hundred and ninety-nine cases with N- breast cancer were evaluated (median follow-up: 60 months). TPA was measured by an immunoradiometric assay and p53 by an immuno-chemiluminescent assay in tumor cytosol. Multiple correspondence analysis was used to study the associations among variables. Their prognostic role (univariate analysis) and their joint effect (multivariate analysis) on RFS were investigated with Cox regression models. TPA showed a direct association with ER and PgR. Higher p53 values were weakly associated to low values of ER, PgR, and TPA. Younger age was related to low and intermediate values of ER and PgR and to low p53 values, while older age was related to high values of ER. Multivariate analysis showed a significant prognostic impact for pT, age, ER, and TPA. Among the interactions considered clinically relevant, only that between ER and age was found. RFS estimated values were poorer in cases with lower than in those with higher TPA values, both in patients expected to have a poor (pT2, young age, low ER) and a better prognosis (pT1, older age, high ER). From the findings of the present study we can draw the following conclusions: The relationship of TPA with prognosis gives an additional contribution to pT, age, and steroid receptors in N- breast cancer; TPA may be considered the first marker of apoptosis measured with a fully standardized quantitative method in tumor cytosol and could be evaluated in prognostic indexes including markers related to different biological mechanisms.
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  • 87
    ISSN: 1573-7217
    Schlagwort(e): reversal ; paclitaxel ; resistance ; P-glycoprotein ; breast cancer ; valspodar ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated 〉6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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  • 88
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 17 (2000), S. 515-520 
    ISSN: 1573-904X
    Schlagwort(e): apoptosis ; cationic liposome ; B cell ; WEHI 231 ; reactive oxygen species
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Liposomes are of considerable interest as drug carriers andimmunoadjuvants. However, few investigators have studied thechanges exerted by liposomes in the cells with which they interact.The purpose of this study was to investigate whether liposomes induceapoptosis in B cells. Methods. The mouse immature B cell line WEHI 231 cells and mousesplenic B cells were treated with liposomes, and the induction ofapoptosis was evaluated by monitoring changes in DNA content, DNAfragmentation and chromatin condensation by flow cytometry, agarosegel electrophoresis and by morphological investigation. Results. Cationic liposomes induced apoptosis in WEHI 231 cells, butneutral and anionic liposomes did not. A contact time of 30 minbetween WEHI 231 cells and cationic liposomes was sufficient toinduce apoptosis, and 80% of the cells showed hypodiploid DNAcontent. Apoptosis induced by cationic liposomes composed ofstearylamine was inhibited by addition of the oxidant scavenger,N-acetyl-cysteine. Conclusions. Cationic liposomes induced apoptosis in WEHI 231 cells,and the production of reactive oxygen species is important in theregulation of apoptosis induced by cationic liposomes. It is well knownthat cationic liposomes show cytotoxicity, and apoptosis may be oneof the causes of this toxicity.
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  • 89
    ISSN: 1573-8469
    Schlagwort(e): apoptosis ; bacteria ; chromatin condensation ; DNA degradation analysis ; plant ; programmed cell death
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Land- und Forstwirtschaft, Gartenbau, Fischereiwirtschaft, Hauswirtschaft
    Notizen: Abstract Ultrastructural details of the hypersensitive reaction induced by infiltration with avirulent race 2 Xanthomonas campestris pv. vesicatoria in pepper ‘Early Calwonder-10R’ leaves (incompatible interaction) are reported. Affected cells displayed plasmalemma undulations and disruption, lysis of the chloroplast membrane, degeneration of other organelles, general cytoplasm disorganisation and, often, protoplast shrinkage. The nuclei contained large masses of electron-dense material, apparently formed by chromatin aggregation. In many cases a single chromatin-like layer was deposited on the inner side of the nuclear envelope leaving a finely granular matrix in the centre of the nucleus; the nucleolus usually disappeared. The nuclear envelope was sometimes ruptured and the internal matrix leaked into the cytoplasm. The content of many affected cells eventually coagulated and became very electron-dense. The walls often collapsed. All these alterations were especially visible in spongy mesophyll cells at sites where bacteria occurred in the intercellular spaces. Although some of the nuclear and cytoplasmic alterations recall certain aspects of apoptotic cell death, molecular determinations did not reveal any DNA degradation in hypersensitively reacting tissues. The first cell alterations in leaves infected with the virulent bacterial race 1 (compatible interaction) were observed only 27 h after inoculation, when the cytoplasm of some cells showed limited internal disorganisation and plasmolysis at sites where bacterial colonies developed.
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  • 90
    Digitale Medien
    Digitale Medien
    Springer
    Plant molecular biology 44 (2000), S. 255-266 
    ISSN: 1573-5028
    Schlagwort(e): abscisic acid ; apoptosis ; gibberellic acid ; nuclease ; programmed cell death ; protease
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract Progress in understanding programmed cell death (PCD) in the cereal aleurone is described. Cereal aleurone cells are specialized endosperm cells that function to synthesize and secrete hydrolytic enzymes that break down reserves in the starchy endosperm. Unlike the cells of the starchy endosperm, aleurone cells are viable in mature grain but undergo PCD when germination is triggered or when isolated aleurone layers or protoplasts are incubated in gibberellic acid (GA). Abscisic acid (ABA) slows down the process of aleurone cell death and isolated aleurone protoplasts can be kept alive in media containing ABA for up to 6 months. Cell death in barley aleurone occurs only after cells become highly vacuolated and is manifested in an abrupt loss of plasma membrane integrity. Aleurone cell death does not follow the apoptotic pathway found in many animal cells. The hallmarks of apoptosis, including internucleosomal DNA cleavage, plasma membrane and nuclear blebbing and formation of apoptotic bodies, are not observed in dying aleurone cells. PCD in barley aleurone cells is accompanied by the accumulation of a spectrum of nuclease and protease activities and the loss of organelles as a result of cellular autolysis.
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  • 91
    ISSN: 1573-4919
    Schlagwort(e): endosulfan ; cytotoxicity ; mitochondria ; apoptosis ; Jurkat cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract Several organochlorinated pesticides including DDT, PCBs and dieldrin have been reported to cause immune suppression and increase susceptibility to infection in animals. Often this manifestation is accompanied by atrophy of major lymphoid organs. It has been suggested that increased apoptotic cell death leading to altered T-B cell ratios, and loss of regulatory cells in critical numbers leads to perturbations in immune function. The major objective of our study was to define the mechanism by which endosulfan, an organochlorinated pesticide, induces human T-cell death using Jurkat, a human T-cell leukemic cell line, as an in vitro model. We exposed Jurkat cells to varying concentrations of endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell growth in a dose- and time-dependent manner. DAPI staining was used to enumerate apoptotic cells and we observed that endosulfan at 10-200 μM induced a significant percentage of cells to undergo apoptotic cell death. At 48 h, more than 90% cells were apoptotic with 50 μM of endosulfan. We confirmed these observations using both DNA fragmentation and annexin-V binding assays. It is now widely being accepted that mitochondria undergo major changes early during the apoptotic process. We examined mitochondrial transmembrane potential (ΔΨm) in endosulfan treated cells to understand the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical exposure, a significant percentage of cells exhibited a decreased incorporation of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the disruption of ΔΨm. This drop in ΔΨm was both dose- and time-dependent and correlated well with other parameters of apoptosis. We also examined whether this occurred by the down regulation of bcl-2 protein expression that is likely to increase the susceptibility of Jurkat cells to endosulfan toxicity. Paradoxically, the intracellular expression of bcl-2 protein was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis occurred by a non-bcl-2 pathway. Based on these data, as well as those reported elsewhere, we propose the following sequence of events to account for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation → excess ROS production → GSH depletion → oxidative stress → disruption of ΔΨm → release of cytochrome C and other apoptosis related proteins to cytosol → apoptosis. This study reports for the first time that endosulfan can induce apoptosis in a human T-cell leukemic cell line which may have direct relevance to loss of T cells and thymocytes in vivo. Furthermore, our data strongly support a role of mitochondrial dysfunction and oxidative stress in endosulfan toxicity.
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  • 92
    ISSN: 1573-4919
    Schlagwort(e): etoposide ; Bcl-XL ; Bax ; apoptosis ; K562 cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie , Medizin
    Notizen: Abstract Etoposide is a potent anticancer agent that is used to treat various tumors. We have investigated the dose-dependent effect of etoposide on apoptosis using chronic myeloid leukemia K562 cells treated with low (5 μM) or high (100 μM) concentrations of the drug. At a low concentration, etoposide induced little apoptosis at 24 h, while about 20% of the cells showed apoptosis morphologically at a high concentration. Processing of caspase-3 was slightly detected from 12 h and became obvious at 24 h with 100 μM etoposide. Caspase-3-like protease activity was detected at 24 h with a high concentration. Moreover, these changes were accompanied by cleavage of poly ADP ribose polymerase (PARP). Changes of the mRNA levels of most apoptosis-regulating genes were not prominent at both concentrations, except for the rapid induction of c-IAP-2/HIAP-1 and the down-regulation of Bcl-XL by 100 μM etoposide. The downregulation of Bcl-XL protein occurred from 6 h, while Bax protein conversely showed a slight increase from 6 h. Taken together, the present findings show that the dose-dependent apoptotic effect of etoposide is based on a change in the balance between Bcl-XL and Bax, which precedes the activation of caspase-3.
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  • 93
    ISSN: 1573-4978
    Schlagwort(e): apoptosis ; CD95 ; human hepatoma cell ; hydrogen peroxide ; p53
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. Direct exposure of human hepatoma cell line SMMC-7221 to hydrogen peroxide (H2O2) can induce apoptosis characterized by morphological evidence and fragmentation of DNA assayed by terminal deoxynucleotidyl transferase assay (TUNEL assay). Analysis of flow cytometry indicated that H2O2 can decrease the level of CD95(APO-1/Fas), and it is confirmed that H2O2 can also activate the differential expression of some specific gene such as p53 by means of RT-PCR technique. The results indicated that CD95 signal transduction system may be involved in the H2O2-induced apoptosis, and can regulate some specific genes associated with apoptosis in transcription and translation levels such as p53.
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  • 94
    Digitale Medien
    Digitale Medien
    Springer
    Digestive diseases and sciences 45 (2000), S. 291-297 
    ISSN: 1573-2568
    Schlagwort(e): apoptosis ; pit cell lineage ; caspase ; gastric mucosal cells
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The purpose of this study was to elucidate the mechanism of spontaneous and rapid cell death of cultured gastric pit cells. Gastric pit cells have a rapid cell turnover rate in vivo. We here show that guinea pig gastric pit cells in culture undergo spontaneous and rapid apoptotic DNA fragmentation, which may represent the rapid cell turnover cycle of gastric pit cells in vivo. This spontaneous apoptotic DNA fragmentation required the presence of fetal calf serum in the culture media. Furthermore, the spontaneous apoptotic DNA fragmentation was prevented by protein synthesis and caspase inhibitors.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 95
    ISSN: 1573-2568
    Schlagwort(e): Helicobacter pylori ; chronic gastritis ; Fas receptor ; Fas ligand ; immune privilege ; apoptosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract H. pylori infection almost invariably results in chronic gastritis, but only a proportion of patients develops severe destruction of epithelial glandular structure or peptic ulcer. To confirm the recent data obtained in testis and eye, showing that Fas ligand is involved in the phenomenon of “immune privilege,” expression of Fas receptor and its ligand of the stomach was investigated in a panel of gastric biopsies obtained from patients H. pylori-positive (N = 42) and with H. pylori-negative (N = 18) by two-color flow cytometry. The results show that membrane-bound Fas ligand protein is constitutively expressed on freshly isolated human gastric mucosal epithelium coupled with infiltrating lymphocytes. There was significant overexpression of Fas receptor and its ligand, and a higher frequency of apoptotic cell death detected by TUNEL in epithelium and infiltrating lymphocytes in H. pylori-infected patients. These findings suggest that involvement of Fas receptor and its ligand system contributes to some extent to mucosal damage in H. pylori-associated gastritis. However, the more specific findings are apoptotic depletion of invading mucosal lymphocytes associated with Fas ligand expression by gastric epithelium. These provide the first direct quantitative evidence to support Fas receptor counterattack and/or paracrine fratricide as a mechanism of immune privilege in vivo in the H. pylori-infected glandular stomach.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 96
    Digitale Medien
    Digitale Medien
    Springer
    Reviews in endocrine & metabolic disorders 1 (2000), S. 183-196 
    ISSN: 1573-2606
    Schlagwort(e): thyroid cancer ; gene mutations ; oncogenes ; tumor suppressor genes ; cell cycle control ; apoptosis ; growth factors ; differentiation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 97
    ISSN: 1573-2568
    Schlagwort(e): cholangiocellular carcinoma ; p53 ; proliferation markers ; apoptosis ; histopathological parameters ; prognosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract This study was performed to examine the correlation between mutations of the p53 tumor suppressor gene, the occurrence of apoptosis, and proliferation in cholangiocellular carcinoma of the liver. The results obtained were compared with pathohistological stage (according to UICC) and grade and with disease related survival rate. In 41 curatively (R0−) resected intrahepatic cholangiocellular carcinomas, the status of the p53 gene was determined by direct sequencing of exons 4–9 and immunohistochemically. Apoptosis was assessed using the in situ end labeling (ISEL) technique in combination with morphological criteria. Proliferation was analyzed by immunohistochemistry of MIB-1 (Ki-67), Proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), grade, several other histopathological factors, and survival rate. Mutations of p53 were detected in 15/41 carcinomas examined (37%). The most common change was a G→C and C→T transition, changing the hot spot amino acid determined by exons 4–8. Of these 15 tumors, 14 were also p53-positive by immunohistochemistry. In each carcinoma examined, we could demonstrate MIB-1, PCNA, and AgNOR dots and also apoptotic cells in variable proportions. The proliferation markers showed a significant correlation among themselves. In univariate survival analysis, the extent of the primary tumor, lymph node status, grade, and p53 were significant factors influencing patient survival. Performing multivariate Cox regression survival analysis, however, only the extent of primary tumor and lymph node status had an independent prognostic impact. Apoptosis was not related to patient prognosis or to other parameters examined. In conclusion, these results indicated that p53 could serve as an additional prognostic parameter that could provide auxiliary information for patient outcome. However, tumor stage and lymph node involvement were the strongest prognostic factors. We failed to establish apoptosis or other pathological parameters as factors predicting the prognosis of patients with cholangiocellular carcinoma.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 98
    ISSN: 1573-2568
    Schlagwort(e): burns ; starvation ; gut ; apoptosis ; proliferation ; rats
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Maintenance of gut mucosal homeostasis depends on a balance between cell proliferation and cell death. Gut mucosal integrity is impaired after severe burn and during starvation. We determined the effect of burn, starvation, and the combination of both on small bowel epithelial apoptosis and proliferation. Fifty adult male Fischer 344 rats (260–300 g) received a 60% full-thickness scald burn and were randomly divided into fed and starved groups. Small intestine was taken at 12, 24, and 48 hr after injury. All animals in the 12-hr group were starved while recovering from anesthesia. Apoptosis was quantified by immunohistochemical staining (TUNEL) and mucosal proliferation was determined by bromodeoxyuridine (BrdU) incorporation. The apoptotic index was higher in burned rats compared to controls at 12 hr after burn; both these groups were starved (P 〈 0.05). At 24 and 48 hr after burn, apoptosis was highest in the starved groups, with no additional effects of burn (P 〈 0.05). Mucosal epithelial cell proliferation was not different between groups at any time point. In conclusion, burn and starvation both increase apoptosis in the small bowel mucosa; however, these effects are not additive. Apoptosis could be attenuated by enteral feeding, which delineates the importance of early enteral feeding initiation after injury to maintain mucosal integrity.
    Materialart: Digitale Medien
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  • 99
    ISSN: 1573-2568
    Schlagwort(e): apoptosis ; cyclooxygenase-2 ; gastric epithelial cells ; Helicobacter pylori ; prostaglandin E2
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Helicobacter pylori induces apoptosis and alters the proliferation of gastric mucosal epithelial cells. Cyclooxygenase-2 (COX-2), the inducible form of prostaglandin (PG) synthesis, is known to cause alteration in epithelial cell growth. The goal of this study was to determine whether COX-2 gene expression by H. pylori infection could influence gastric epithelial cell apoptosis. Expression of COX-2 mRNA and proteins was up-regulated in Hs746T gastric epithelial cell lines infected with H. pylori, when assessed by quantitative RT-PCR and western blot. Inhibition of COX-2 expression using NS-398, a specific COX-2 inhibitor, showed a significant increase of gastric epithelial cell apoptosis and caspase-3 activation in Hs746T cells infected with H. pylori. Moreover, the effect of NS-398 on H. pylori-induced apoptosis was reversed by the addition of PGE2. These results suggest that up-regulated COX-2 expression by H. pylori infection can inhibit apoptosis of gastric epithelial cells.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 100
    ISSN: 1573-2568
    Schlagwort(e): chemoprevention ; colorectal cancer ; 5-aminosalicylic acid ; olsalazine ; apoptosis ; bromdeoxyuridine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.
    Materialart: Digitale Medien
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