Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0.9 and 4.6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient. In an in vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue.
Cytosine arabinoside (ara‐C) and etoposide are often used in combination in the treatment of acute myelocytic leukemia (AML). The intracellular phosphorylation of ara‐C to its 5′‐triphosphate (ara‐CTP) is a prerequisite for its cytotoxic effects. It has been shown in vitro that etoposide can impair the formation of ara‐CTP in leukemia cells. The present study was undertaken in order to elucidate whether this interaction may be of clinical importance. Leukemia cells were isolated from 3 patients with acute myelocytic leukemia and incubated in medium (RPMI‐1640) with or without 10% fetal calf serum or in human plasma. When the cells were incubated in RPMI‐1640 with ara‐C (10 μmol/l) and etoposide during 2 h, the formation of ara‐CTP was decreased to 71 ± 18 (mean ± S.D.) and 30 ± 15% of control at 1 and 10 μg/ml etoposide, respectively. When the cells were incubated in human plasma, the formation of ara‐CTP was not influenced by the presence of etoposide (101 ± 6 and 103 ± 20% at 1 and 10 μg/ml etoposide). When incubated in RPMI supplemented with 10% fetal calf serum, the corresponding figures were 81 ± 8 and 70 ± 20%. Six patients with AML were therefore treated with ara‐C 0.5 or 1.0 g/m2 as a 2‐h infusion every 12 h and, during 1 h before the second ara‐C infusion, 100 or 200 mg/m2 etoposide was administered. The median change in the AUC of cellular ara‐CTP between the first and second ara‐C dose was 0% (‐37 to +21%). The corresponding median change in rate of accumulation of ara‐CTP in leukemia cells was 12% (‐26 to +110%). The concentration of etoposide in plasma during the ara‐C infusion was 18.7 ± 5.1 μg/ml while the non‐protein bound etoposide was 0.73 ± 0.34 μg/ml. Thus, despite exposure to higher etoposide concentrations in vivo than in vitro, no impairment of ara‐CTP formation was seen in the patients. This corresponds to the results obtained when leukemic cells were incubated in plasma. It is concluded that the inhibition of ara‐CTP formation by etoposide seen in vitro is offset by the high protein binding of etoposide in plasma (96%) and that etoposide does not impair the formation of ara‐CTP in leukemia cells in vivo during treatment with standard‐dose etoposide.
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