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  • 1
    ISSN: 1432-0843
    Keywords: 5-fluorouracil ; Anabolites ; 5-fluorouridine ; 5-fluoro-2′-deoxyuridine ; Breast cancer ; Toxic side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2′-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by highperformance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUCFUrd) and for FdUrd (AUCFdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUCFUrd values (mean±SEM, 2.9±0.7 μg ml−1 h) and high AUCFdUrd values (14.1±2.7 μg ml−1 h), respectively, whereas courses with myelosuppression (WHO grades 2–4) showed inverse profiles with high AUCFUrd values (16.3±2.3 μg ml−1 h) and low AUCFdUrd values (3.1±1.0 μg ml−1 h), respectively. A statistically significant difference in AUCFdUrd values was also observed between cycles with and those without mucositis (P=0.0027), with AUCFdUrd values being 22.6±5.6 and 7.8±1.9 μg ml−1 h, respectively. Whereas hematotoxicity could be correlated with both AUCFUrd and AUCFdUrd values, mucositis was associated with high AUCFdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P=0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Keywords: Key words 5-Fluorouracil ; Anabolites ; 5-Fluorouridine ; 5-Fluoro-2′-deoxyuridine ; Breast cancer ; Toxic side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This paper describes the relationship between 5-fluorouracil (FUra)–derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2′-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2) . A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by high-performance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUCFUrd) and for FdUrd (AUCFdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUCFUrd values (mean ± SEM, 2.9±0.7 μg ml-1 h) and high AUCFdUrd values (14.1±2.7 μg ml-1 h) , respectively, whereas courses with myelosuppression (WHO grades 2–4) showed inverse profiles with high AUCFUrd values (16.3±2.3 μg ml-1 h) and low AUCFdUrd values (3.1±1.0 μg ml-1 h), respectively. A statistically significant difference in AUCFdUrd values was also observed between cycles with and those without mucositis (P=0.0027), with AUCFdUrd values being 22.6±5.6 and 7.8±1.9 μg ml-1 h, respectively. Whereas hematotoxicity could be correlated with both AUCFUrd and AUCFdUrd values, mucositis was associated with high AUCFdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P=0.002) , indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Flow cytometric determination of time dependent changes of numbers of reticulocytes in peripheral blood were investigated as a parameter for changes in erythropoiesis induced by radiation- or chemotherapy. Rats irradiated or treated with drugs (such as e.g. cyclo-phosphamide 100 mg/kg, vincristin 0.2 mg/kg, or mitomycin C 1.0 mg/kg) showed clear changes in erythropoietic activity. Reticulocyte numbers decreased rapidly until day 3–4 after treatment; this period was followed by a gradual increase and normal control values were seen at day 8–11. Radiation effects of doses as low 0.5 Gy could be detected in such a way. Similar studies were performed with patients with ovarian tumors treated with cis-platinum, a drug that may cause non-immune haemolysis. During prolonged treatment some patients showed increasing numbers of reticulocytes, measured at the first day of each hospitalization period, whereas leucocyte and platelet counts stayed more or less constant. Increasing numbers of reticulocytes generally indicates stimulation of erythropoietic activity of the bone marrow (due to increased blood loss); in this study increasing numbers often preceeded a decrease in hemoglobin values later on. Flow cytometric analysis of reticulocytes is therefore a potentially useful tool to detect changes in erythropoiesis, and considered more sensitive for the early recognition of patients that develop anemia, than hemoglobin measurements only.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1335
    Keywords: Cyclosporin A ; Multidrug resistance ; P glycoprotein ; Chemosensitizing ; In vivo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorbicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg−1 day−1. This resulted in whole-blood CsA levels above 2 μmol/l, while intratumoral CsA levels amounted to 3.6 μmol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2013
    Keywords: colon cancer cells ; mdr-1 ; volume-activated chloride-currents ; patch clamp ; RT-PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Correlation between expression of the mdr-1 genes (a and b) at the mRNA and protein level and volume-activation of chloride-channels was studied in rat colon cancer CC531 cells by means of RT-PCR, Western blotting and patch clamp, respectively. Three different kinds of cell lines were used: CC531-PAR, CC531-COL and CC531-REV. At the mRNA level, the parental cell line CC531-PAR showed significantly less mdr-1a expression in comparison with CC531-COL, a drug-resistant cell line induced from the parental CC531 cells by growth in the presence of colchicin. The third cell line, CC531-REV, was a spontaneous revertant of the drug-resistant cell line to a drug-sensitive one, but with a maintained level of mdr-1a mRNA. In none of the three cell lines, mdr-1b mRNA could be detected At the protein level, a clear difference in mdr1 expression between CC531-PAR/REV and CC531-COL was observed. Although the amount of mdr-1a mRNA detected in CC531-REV was comparable to that found in CC531-COL, the amount of mdr-1 encoded protein in CC531-REV was remarkably reduced. In all three cell types, cell swelling activated chloride-currents which could be blocked by NPPB. Chloride-currents measured at the K+ reversal potential of-90 mV were not significantly different (−86.1±19.1 pA/pF, n=5 in CC531-PAR, −59.5±13.1 pA/pF, n=6 in CC531-COL and −68.1±15.3 pA/pF, n=7 in CC531-REV). It is proposed that the mdr-1 genes do not code for the volume-activated chloride-current in these rat colon cancer cells.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1569-8041
    Keywords: biological transport ; blood specimen collection ; erythrocytes ; ifosfamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Oxazaphosphorines are metabolised by a variety of pathways, one of which leads to activation and the formation of alkylating compounds. However, the transport forms conveying activated oxazaphosphorines to the tumour cell have not been fully characterised. There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma. We have now determined the concentrations of ifosfamide and seven of its metabolites in the plasma and erythrocytes of patients receiving a six-hour intravenous infusion of ifosfamide. Patients and methods: Red cells from five patients, receiving a total of eight cycles of ifosfamide, were separated from plasma using the MESED instrument, and analysis of red cells and plasma performed using Gas Chromatography-Mass Spectrometry (GC/MS). Results: The concentration of all compounds in the erythrocyte compartment was higher than or equal to those in plasma, and isophosphoramide mustard and carboxyifosfamide showed a particular affinity for the erythrocyte. The red cell fraction can contain as much as 77% of the total blood concentration of isophosphoramide mustard. Conclusions: Erythrocyte associated isophosphoramide mustard is an important transport form of activated ifosfamide. Red cells may have a role in the delivery of activated oxazaphosphorines to tissues.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: angiogenesis ; biological monitoring ; platelets ; vascular endothelial growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Serum VEGF levels are elevated in cancer patients and are used as a tumor marker in different malignancies. We have measured VEGF levels in different blood compartments in cancer patients and healthy volunteers in order to assess the most suitable way of processing blood for measuring VEGF as a marker of tumor-angiogenesis. Patients and methods: VEGF concentrations were analyzed by an enzyme-linked immunosorbent assay in serum (VEGFS), EDTA plasma (VEGFEDTA), citrated plasma (VEGFC), CTAD-plasma (VEGFCTAD), platelet poor plasma (VEGFPPP), platelet rich plasma after induction of platelet activation (VEGFPRP). Platelet activation was assessed by measuring PF4 concentrations in different plasma samples. Results: We observed higher VEGFS (P = 0.0027), VEGFEDTA (P = 0.003) and VEGFPPP (P = 0.0007) levels in cancer patients than in volunteers; VEGFPRP concentrations showed no significant difference (P = 0.208). Analysis of the correlation between VEGFplt and VEGFS in cancer patients showed a similar correlation in a comparable VEGFS concentration range as in the volunteers. When comparing VEGFC to VEGFCTAD, we find significantly higher VEGF and PF4 levels in citrated plasma (VEGF: P = 0.00019; PF4: P = 0.00023). Conclusions: It is likely that VEGFS in cancer patients encompass platelet-delivered VEGF and VEGF from other sources, notably from (neo)-angiogenesis in tumoral tissue. The best discrimination between volunteers and cancer patients was observed in PPP. As generating plasma can induce platelet activation, with consequent VEGF release from platelets, we suggest that to assess free circulating VEGF, CTAD plasma should be used.
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  • 8
    ISSN: 1434-0879
    Keywords: Mitomycins ; Bladder ; Systemic uptake ; Toxicity ; Urothelium ; Dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was designed to evaluate the local effects of the new mitomycin C analogue KW-2149 after intravesical instillation, together with its penetration into the systemic circulation in healthy beagle dogs. Two reference dogs were treated with two instillations of mitomycin C (30 mg in 30 ml phosphate buffer). Four dogs were given two, three, four and six instillations, respectively, of KW-2149 (60 mg in 30 ml phosphate buffer). KW-2149 concentrations measured in the systemic circulation were very low and were frequently found to be below the limit of determination. The number of instillations had no influence on the KW-2149 concentrations measured in the systemic circulation. Blood analysis showed no systemic toxicity. The histopathological findings in the bladder were comparable in both groups. The number of instillations had no influence on the severity of the lesions found in the bladder wall. On the basis of its in vitro activity KW-2149 can be regarded as a promising agent for intravesical treatment of superficial bladder cancer.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-739X
    Keywords: Administration, intravenous ; Administration, oral ; Biological availability ; Clinical trials ; Cyclophosphamide ; Drug interactions ; Fluorouracil ; Methotrexate ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m2, methotrexate 30 mg/m2 and fluorouracil 500 mg/m2 (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclophosphamide.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Pharmacy world & science 7 (1985), S. 93-99 
    ISSN: 1573-739X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Severalin vivo methods have been assessed for their capacity to predict sensitivity for anticancer agents in humans. Standard strategies have been developed for screening purposes. Adjustments of these strategies are frequently suggested in reports in which the correlation between assay results and clinical therapeutic efficacy is analysed. Low predictivity and high costs of these assays are important reasons for changing the screening strategy.In vivo methods which predict the clinical response in the individual patient, are under investigation. Only the results of the subrenal capsule assay (in normal mice) have been correlated with the clinical response in a larger study. The criticism of the method and the low predictivity for sensitivity in a prospective study provide no reason for optimism. Methods which study changes predicting the clinical response in patients are still in a developmental phase.
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