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  • 1
    Digitale Medien
    Digitale Medien
    Quadruplex DNA formation in a region of the tRNA gene supF associated with hydrogen peroxide mediated mutations (1991)
    s.l. : American Chemical Society
    Biochemistry 30 (1991), S. 8648-8653 
    Details
    ISSN: 1520-4995
    Quelle: ACS Legacy Archives
    Thema: Biologie , Chemie und Pharmazie
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1021/bi00099a022
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  • 2
    Digitale Medien
    Digitale Medien
    DNA base modifications induced in isolated human chromatin by NADH dehydrogenase-catalyzed reduction of doxorubicin (1992)
    s.l. : American Chemical Society
    Biochemistry 31 (1992), S. 3500-3506 
    Details
    ISSN: 1520-4995
    Quelle: ACS Legacy Archives
    Thema: Biologie , Chemie und Pharmazie
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1021/bi00128a026
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  • 3
    Digitale Medien
    Digitale Medien
    Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea (1994)
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 161-164 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Fluorodeoxyuridine ; Folinic acid ; Hydroxyurea
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m−2 day−1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg−1 day−1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 2500 mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00686640
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  • 4
    Digitale Medien
    Digitale Medien
    Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors (1996)
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 254-258 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Hydroxyurea ; Pharmacokinetics ; Toxicity ; Human ; Drug therapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R 2 = 0.71, n = 18, P〈0.0001). The mean±SE concentrations were 93±16, 230±6 and 302±27 μM at 1, 2 and 3.2 g/m2 per day, respectively. The mean±SE renal and nonrenal clearances of hydroxyurea were 2.14±0.18 and 3.39±0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean±SE half-life of 3.25±0.18 h (n = 17). The steady-state concentration of hydroxyurea was 〉200 μM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002800050569
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  • 5
    Digitale Medien
    Digitale Medien
    High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 504-508 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Lung cancer ; Toremifene ; Cisplatin ; Protein kinase C ; Phase II trial
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≥5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1–7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (±8.6) μM and 9.8 (±4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002800050852
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  • 6
    Digitale Medien
    Digitale Medien
    A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 403-410 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Carboplatin ; Etoposide ; Drug resistance ; Modulation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Methods: Patients received intravenous VP-16 (200 mg/m2) and CBDCA (300 mg/m2), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. Results: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m2 (range 0.8–1.5 l/h per m2), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml · min (range 2.4–4.8 mg/ml · min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 μM (range 0.5–2.2 μM) and 4.4 μM (range 1.3–5.9 μM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 μM (range 0.004–0.04 μM). The median CSA level at 24 h of 1450 μg/l (range 1075–1640 μg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. Conclusion: These results demonstrate that in vitro DR- reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002800000142
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  • 7
    Digitale Medien
    Digitale Medien
    Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 19-26 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Methotrexate ; Leptomeningeal carcinomatosis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200–1500 mg/m2, followed by a 23-h infusion of 800–6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 μM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 ± 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 ± 41 ml/min per m2) versus without CNS disease (59 ± 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. Conclusion: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (〉1 μM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002800000118
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  • 8
    Digitale Medien
    Digitale Medien
    Phase I study of mitomycin C and menadione in advanced solid tumors (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 293-298 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words. Mitomycin C ; Menadione ; Phase I studies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1–2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors for which treatment with single-agent mitomycin C is appropriate.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00689046
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  • 9
    Digitale Medien
    Digitale Medien
    Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck (1992)
    Springer
    Cancer chemotherapy and pharmacology 31 (1992), S. 167-169 
    Details
    ISSN: 1432-0843
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00685106
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  • 10
    Digitale Medien
    Digitale Medien
    Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea (1994)
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 161-164 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Fluorodeoxyuridine ; Folinic acid ; Hydroxyurea
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m–2 day–1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg–1 day–1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 2500 mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00686640
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