Acquired drug resistance and cross resistance is the major cause of chemotherapy failure. The overall purpose of our study is to determine the mechanisms of drug resistance in ovarian cancer and to develop clinically feasible techniques to reverse drug resistance. On the basis of preclinical studies, it is our hypothesis that drug resistance in ovarian cancer patients is related to increased cellular levels of glutathione (GSH), increased activity of glutathione S-transferase (GST) and increased ability of tumor cells to repair DNA damage produced by alkylating agents and cisplatin. Furthermore, we have also demonstrated that: (1) pharmacologic depletion of GSH levels with buthionine sulfoximine (BSO) leads to potentiation of cytotoxicity of melphalan and carboplatin, (2) inhibition of GST with ethacrynic acid potentiates the cytotoxicity in vitro and in vivo of bifunctional alkylating agents, and (3) inhibition of DNA repair with aphidicolin potentiates cisplatin cytotoxicity in vitro. In order to test our hypothesis, we plan to obtain specimens serially from ovarian cancer patients undergoing treatment. Biopsies will be obtained before treatment, during treatment, and after the completion of intensive induction chemotherapy regimens and at the time patients become resistant to treatment. These tumor samples will be assayed for those factors which we have identified to be associated with alkylating agent and cisplatin resistance. These include GSH levels, GST activity and isozyme patterns and mRNA expression of isozymes, and expression of mRNA for enzymes which participate in DNA repair (DNA polymerases alpha and beta, ERCC1 and ERCC2). Molecular probes will also be used to determine if drug resistance in ovarian cancer is associated with increased amplification and/or expression of mdr-1, metallothionein, and the HER-2/Neu proto-oncogene. We also propose to perform Phase I and Phase II clinical trials of biochemical modulators of drug resistance. Specifically, we plan to evaluate the ability of; (1) BSO to modulate the cytotoxicity of melphalan and carboplatin, (2) ethacrynic acid to inhibit GST and potentiate the cytotoxicity of thioTEPA, and (3) aphidicolin to inhibit DNA polymerase alpha and thereby decrease DNA repair capacity and increase the efficacy of platinum-containing compounds in drug resistant patients. Pharmacokinetic studies will be performed of the biochemical modulators in all Phase I trials. In addition, tumor biopsy specimens will be obtained in these patients to determine if the intended biochemical modulation is taking place in normal tissues and in tumor cells. Results of these Phase I and II trials will lead to additional clinical trials testing the efficacy of combinations of biochemical modulators of resistance (e.g. BSO plus aphidicolin) in drug resistant patients.
| Johnson, S W; Perez, R P; Godwin, A K et al. (1994) Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines. Biochem Pharmacol 47:689-97 |
| Hamilton, T C; O'Dwyer, P J; Ozols, R F (1993) Platinum analogues in preclinical and clinical development. Curr Opin Oncol 5:1010-6 |
| Schisselbauer, J C; Hogan, W M; Buetow, K H et al. (1992) Heterogeneity of glutathione S-transferase enzyme and gene expression in ovarian carcinoma. Pharmacogenetics 2:63-72 |
| Godwin, A K; Perez, R P; Johnson, S W et al. (1992) Growth regulation of ovarian cancer. Hematol Oncol Clin North Am 6:829-41 |
| Hamilton, T C (1992) Ovarian cancer, Part I: Biology. Curr Probl Cancer 16:1-57 |
