The detoxification mechanisms, modification of cellular respond by altered intercellular redox status, and oxygen metabolism in sensitive and resistant cell. to chemotherapy drug. are of interest to the area of cancer treatment and directly related to our studies. Deleterious species produced by the antineoplastic drugs and cellular response to these species, as well as sulfhydryl containing compounds as they relate to metabolism, activation and detoxification of antineoplastics are being explored. We have demonstrated using compounds which can elevate intracellular glutathione (GSH), an essential redox active molecule, that GSH can play an important role in the detoxification of alkylating agents such as melphalan or metal dependent drugs such as cisplatin. We have demonstrated in mice that injections of GSH after cisplatin treatment can help prevent kidney damage. We have also demonstrated that the GSH elevating agents (monoesters of glutathione) elevate GSH through a pathway which is dependent on the active denovo synthesis of GSH. Because of this, the use of these agents to elevate GSH in bone marrow cells after aklylator treatment to alleviate normal tissue toxicity may not be straightforward. In addition, using the GSH depleting agent, buthionine sulfoximine (BSO), the elevation of GSH by these agents is prevented. Hence, therapies which currently use BSO to sensitize cells to various chemotherapy agents may not be able to take advantage of these class of GSH elevating to again reduce normal tissue toxicity. Because BSO is currently undergoing clinical studies, we are undertaking animal studies to examine the kinetics of GSH depletion in normal and tumor tissue. We will attempt to determine GSH levels on a single cell basis, and hence, see whether the kinetics of GSH depletion is the same in tumor versus normal cells. We will examine other redox pathways such as the P450 reductase system which could detoxify or potentiate chemotherapy agents. We have obtained 3T3 mouse cells which express P450 at greatly elevated levels. We are interested in determine whether the P450 system will alter the toxicity profile of various redox active chemotherapy agents such as adriamycin, mitomycin, or paclitaxel.
