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Summary A panel of doxorubicin-resistant sublines of the human small-cell lung carcinoma cell line GLC4 displays decreasing DNA topoisomerase Ila (TopoIla) mRNA levels with increasing resistance. In the present study we describe how this decrease may be regulated. No significant differences in TopoIla mRNA stability or gene arrangement were found, using mRNA slot-blotting and Southern blotting, in the most resistant cell line compared with the parental cell line. To investigate if Topolla gene copy loss contributed to the mRNA decrease, fluorescence in situ hybridisation using a TopoIllx-specific probe was performed. During doxorubicin resistance development, the composition of the population in each cell line shifted with increasing resistance, from a population in which most cells contain three TopoIla gene copies (GLC4) to a population in which most cells contain only two copies. A partial revertant of the most resistant cell line displayed a shift back to the original situation. We conclude that the Topolla gene copy number decrease per cell line is in good agreement with the decreased TopolIa mRNA and protein levels, and Topoll activity levels in these cell lines which were described previously.

In a P-glycoprotein-negative cell line, GLC4-Adr90, a 75-fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S-transferase (GST) elevated), and a reduced topoisomerase-II (topo-II) activity compared with the parent cell line GLC4. The effect on Adr resistance of buthionine sulfoximine (BSO, GSH synthesis inhibitor), was studied alone or in combination with verapamil (drug-efflux inhibitor), docosahexaenoic acid (membrane lipid domain affector), ethacrynic acid (GST inhibitor), aphidicolin (DNA-polymerase-alpha inhibitor) or novobiocin (NOV, topo-II inhibitor). Cytotoxicity was tested using a microculture tetrazolium assay. In GLC4-Adr90, BSO and NOV increased Adr-induced cytotoxicity 12.9-fold and 1.8-fold respectively. The combination of BSO plus NOV showed an additive effect, decreasing the Adr resistance factor from 75 to 2.7. Combination of modulators of Adr resistance directed at different resistance mechanisms appears promising in vitro.

Summary In phase I studies. lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mgm-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3 4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P<0.0l). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 ± 0.5, 3.0 ± 0.6. and 3.2 ± 1.1 h mgl-' for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 ± 5% and 24 h after infusion 74 ± 3% of the lobaplatin dose was excreted in the urine. In conclusion. lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.Keyword: ovarian cancer; phase II; lobaplatin Over the last decade, treatment of patients with ovarian cancer has been dominated by cisplatin-containing regimens (Neijt et al., 1984;Williams et al., 1985; Omura et al., 1986). Combinations of cisplatin with one single alkylating agent give equivalent results to three-or four-drug schedules, but appear to be less toxic (Neijt et al., 1987). In recent years, the development of new drugs has been directed towards the development of platinum analogues that are equipotent but less toxic than the parent compound. Carboplatin has emerged as leading analogue in this respe-t with reduced nephrotoxicity, gastointestinal toxicity and neurotoxicity (Calvert et al., 1982;Evans et al., 1983). Myelotoxicity, especially thrombocytopenia. has been found to be the doselimiting toxicity of carboplatin. Especially in ovarian cancer, carboplatin appears to have equivalent activity to cisplatin (Alberts et al., 1992;Swenerton et al., 1992).An important direction in current r...

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