The long term scientific goal of this proposal is to gain an understanding of how the nitroimidazole sensitizers may enhance the activity of anticancer drugs, and to apply that knowledge in designing novel regimens for the treatment of resistant tumors. Most solid tumors have a significant proportion of hypoxic cells, a consequence of abnormal vascular development in malignant tissue. Hypoxic cells are resistant to both radiation and to chemotherapeutic drugs, especially alkylating agents. A group of xenobiotic-scavenging enzymes, the glutathione-S-transferases (GST's) are expressed at higher levels in cells exposed to hypoxia. 2- Nitroimidazoles have been identified as a class of compounds which in vitro and in vivo restore the sensitivity of hypoxic cells to both radiation and chemotherapy. OF the congeners evaluated to date, SR2508 has the highest therapeutic index of this class of drugs. We hypothesize that the sensitizing action of SR2508 is closely related to its inhibition of GST's and depletion of glutathione. To test these hypotheses, in preclinical models, we will (a) characterize the kinetics of inhibition by SR2508 of GST's using purified enzyme in vitro, and whole cells in culture, under both oxic and hypoxic conditions; (b) define the dose-response and time- course of GST inhibition and glutathione (GSH) depletion by SR2508 in tumors and normal tissues of tumor bearing scid mice; (c) detect and quantify glutathione adducts of SR2508 in tumor and normal tissues. In a series of clinical trials. Ultimately leading to a definitive test of chemosensitization by SR2508, we plan to (a) define the dose and schedule of SR2508 for use in combination with cyclophosphamide at standard doses; (b) describe the combination of SR2508 and cyclophosphamide at high alkylating agent doses in association with autologous bone marrow transplantation. The results of these studies will, it is hoped, clarify aspects of the cellular action of SR2508, and indicate how clinical regimens should be designed to maximize their potential role in therapy.
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