This application is for the continuation of studies to design and develop inhibitors of O6-alkylguanine-DNA alkyltransferase (AGT) as chemotherapeutic agents. The presence of AGT is a major factor in the resistance of tumor cells to killing by drugs that form adduct at the O6- position of guanine. The aim of these studies is to extend the effectiveness and the range of tumors that can be treated with these drugs. Studies during the first period of support have led to Phase I trials with O6-benzylguanine (BG) but further work is needed to optimize the use of this agent and to develop compounds with better therapeutic properties in order to improve the discrimination between tumors and normal tissue. There are 5 laboratory programs and 3 cores. Dr. A.E. Pegg will serve as the PI and the Leader of Program 1 which will carry out studies on the interaction of possible AGT inhibitors with the control and mutant AGT proteins and design improved inhibitors including compounds able to inactivate BG-resistant AGTs. Dr. M.E. Dolan will head Program 2 in which detailed metabolic studies of novel AGT inhibitors will be carried out. Specific compounds include:metabolism-resistant 8-substituted BG derivatives; compounds with ester linkages that are activated as AGT inhibitors by esterases; and benzyl pyrimidine derivatives which are very potent but rapidly cleared. The use of regional therapy with AGT inhibitors using intraarterial delivery for CNS parenchymal tumors and intrathecal administration for leptomengeal neoplasms and the selection of the most promising compounds for targeting the inhibitor to brain tumors will be studied in Program 3 led by Dr. H.S. Friedman. Program 4 led by Dr. S.C. Schold will focus on the development of 9-substituted BG derivatives including the nucleoside and deoxynucleoside which appear to offer significant advantages over BG in terms of systemic availability, penetration of the blood-brain barrier and localized metabolic activation. Program 5 led by Dr. S.L Gerson will investigate methods for optimizing tumor cytotoxicity after AGT inactivation. He will study the extent of AGT inactivation needed to achieve maximal inactivation, methods to overcome resistance to BG-therapy of colon and breast tumors, and procedures including gene transfer to minimize bone marrow toxicity of the combination of AGT inhibitors and BCNU. Routine evaluation of compounds both for AGT inactivation and for the ability ot sensitize tumor cells in culture to BCNU will be carried out in Core B led by Dr. Pegg. Promising compounds will be examined for in vivo pharmacokinetics, tumor AGT inactivation and sensitization of tumor xenografts in nude mice in Core C led by Dr. Dolan.
|Effective start/end date||8/17/92 → 9/29/01|