The proposed experiments are designed to evaluate buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, as a potential adjuvant to radiation and chemotherapy. The effects of GSH depletion on tumor cell killing by chemotherapy agents and radiation will be studied in mice and the possibility of increased normal tissue toxicity, primarily to bone marrow, will be investigated. The results will assist in assessing a possible role for thiol depletion in cancer therapy. To do this, the rate and extent of GSH depletion following BSO administration will be compared among normal tissues and a transplantable tumor in mice. Next, the effects of GSH depletion on chemical or radiation-induced cell killing of mouse tumor and bone marrow cells will be compared. Following depletion of GSH in vivo, mice will be treated with cytotoxic agents and survival of tumor cells and bone marrow cells will be determined. Alternatively, tumor cells and bone marrow cells that have been isolated from control or BSO-treated mice will be exposed to chemotherapy drugs or radiation in vitro, then assayed for survival. Comparison of these two treatment protocols may differntiate between purely biochemical effects of thiol depletion and physiological or pharmacological effects only seen with in vivo treatment. The effects of extreme thiol depletion will be studied and then, where appropriate, the extent of GSH depletion will be correlated with the degree of cell killing. These studies may be extended to include other tissues known to be sensitive to specific agents, e.g., kidney (cis-Pt[II]) and intestinal mucosa (X-radiation).
