There is compelling evidence indicating that the presence in tumor cells of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, imparts resistance to chemotherapeutic chloroethylating and methylating agents. This proposal has as its main themes the development of ways to minimize this resistance and exploitation of the absence of this activity to increase the general effectiveness of these agents. The experiments will address several questions needed to achieve this objective and will focus on: (a) testing whether O6-benzylguanine is a useful agent for this purpose; (b) developing other alkyltransferase inactivators that may have greater potency or better selectivity towards tumor cells than O6- benzylguanine; (c) examining alternative methods of reducing alkyltransferase levels and testing the regulation of alkyltransferase levels in response to inhibitors and therapeutic agents; and (d) studying the distribution of alkyltransferase in tumors to provide a method to identify those tumors for which alkyltransferase inactivation will be beneficial. There are 6 programs. Dr. A.E. Pegg will serve as the Principal Investigator and the Leader of Program 1 which will carry out biochemical studies to design, synthesize and test compounds which inactivate the alkyltransferase. Dr. R.C. Moschel will serve as a collaborator for this section and will synthesize compounds as alkyltransferase inhibitors. Dr. M.E. Dolan will serve as the leader of Program 2 and will examine the metabolic stability and uptake of these inhibitors and test their effects on the response of melanomas and lung tumors to alkylating agents. In Program 3, Dr. D.B. Yarosh will use immunohistochemical techniques to study the distribution of alkyltransferase in tumors and the response to inhibitors and chemotherapy. He will also investigate whether an antisense approach to reduction of the alkyltransferase levels is valuable. In program 4, Dr. L.C. Erickson will investigate the regulation of the alkyltransferase levels and the synergism between treatments involving chloroethylating agents, streptozotocin and depletion of alkyltransferase. In program 5, Dr. S.L. Gerson will test the efficacy of inhibiting alkyltransferase as a means to enhance the chemotherapeutic effectiveness of alkylating agents against breast cancer. He will also investigate methods to protect normal myeloid cells and precursors. In program 6, Drs. S.C. Schold and H. Friedman will study the use of alkyltransferase inactivation in improving the therapy of brain tumors by alkylating agents and test whether intrathecal administration of the inhibitors improves the therapeutic efficacy.
