The biology and chemosensitivity of ovarian cancer in vivo and in vitro

Abstract

Drug resistance to alkylating agents is known to be a major clinical problem in the management of patients with ovarian cancer. In a randomised clinical trial of 70 patients with advanced ovarian cancer the question was asked if this resistance could be overcome by a three drug combination, when compared to conventional management with a single alkylating agent. Cisplatin, adriamycin and cyclophosphamide given together achieved a complete clinical response rate of 67%, while oral thloranbucil alone gave a response rate of only 30%. The median survival was 17 months in the combination arm, and 11.8 months in the chlorambucil arm, but these differences were not significant (p - 0.84) and toxicity was considerably greater in the combination arm. More effective induction regimes are required to improve the outlook in ovarian cancer. To examine the possible mechanisms of this drug resistance at the cellular level, a suitable tumour model system was required, and using the mouse M5076 ascites carcinoma, correlation was obtained between in vitro drug sensitivity curves assessed by clonogenic assay and the in v voi sensitivity in the mouse as well as the peak achievable plasma level in man. However, the M5076 was subsequently shown to have morphological and immunological features consistent with a histiocytic lymphoma. The use of primary cultures of human ovarian tumour specimens in soft agar was also assessed but these studies were not continued because of poor growth and low cloning efficiency. The most satisfactory model for the study of cellular pharmacology was found to be human ovarian cancer cell lines. Four fold resistance was developed to the alkylating agent melphalan by stepwise incubation with increasing concentrations of the drug, and the degree of resistance achieved was found to be similar to that observed in the lines derived from clinically resistant patients. Cross resistance to cisplatin and thiotepa was observed, but not to adriamycin. The uptake of melphalan by the sensitive cells and those in which resistance had been induced was found to be identical, and the resistant line dechlorinated as much melphalan to the inactive hydroxymetabolites as the sensitive line. Glutathione levels, however, were two fold higher in the resistant compared to the sensitive cells, and glutathione depletion either by omission of cysteine from the medium or preincubation with buthionine sulphoximine, a specific inhibitor of glutathione synthesis, was found to sensitise the resistant cells to melphalan. Buthionine sulphoximine at a dose of 50,44 for 18 hours was minimally cytotoxic to the resistant cells when given alone, and reversed the degree of acquired resistance. It is concluded that the level of intracellular glutathione may be associated with resistance to melphalan, and that depletion of this thiol by the synthetic amino acid buthionine sulphoximine may have a role in the modulation of alkylating agent activity in human ovarian cancer.

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