Acquired drug resistance and cross resistance is the major cause of chemotherapy failure. The overall purpose of our studies is to determine the mechanisms of drug resistance in ovarian cancer and to develop clinically feasible techniques to reverse drug resistance. We have established that drug resistant human ovarian cancer cells have higher levels of cellular glutathione (GSH) compared to drug sensitive cell lines. Furthermore, pharmacologic depletion of GSH levels with Buthionine Sulfoximine (BSO) leads to potentiation of cytotoxicity of melphalan in vitro and in vivo. The mechanisms by which GSH confers resistance to alkylating agents and cisplatin remain to be established. However, we have recently demonstrated that drug resistant ovarian cancer cell lines have an increased capacity to repair DNA damage. We will conduct a Phase I trial of BSO plus melphalan in drug resistant cancer patients. We plan to: (1) Determine the toxicity of BSO given as multiple I.V. doses. (2) Determine if GSH levels in tumor cells and peripheral lymphocytes can be lowered by BSO. (3) Establish the relationship between peripheral lymphocyte levels and tumor GSH levels. (4) Assess the toxicity and efficacy of the combination of BSO given as multiple I.V. doses followed by a single dose of I.V. melphalan. (5) Determine the plasma pharmacokinetics of BSO. This study represents the first attempt to clinically manipulate cellular GSH levels as a means to reverse drug resistance. The biochemical and pharmacokinetic measurements in this trial will be necessary for the design of the optimal regimen for Phase II clinical development of BSO. Our pre-clinical studies will examine additional potential strategies focused upon pharmacologically reversing drug resistance in relevant in vitro and in vivo models systems of human ovarian cancer which we have previously developed. We will examine: (1) The effect of lowering GSH upon carboplatin activity. (2) The effect of inhibition of DNA repair with aphidicolin upon the cytotoxicity in vitro and in vivo of melphalan and platinum containing drugs. (3) The effect of combining depletion of GSH with inhibition of DNA repair upon cytotoxicity of platinum containing compounds and bifunctional alkylating agents. The results of these studies will lead to additional clinical trials testing whether drug resistance can be reversed by pharmacologic techniques.
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