RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS

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This is one of a trilogy of applications of collaborative research with a common theme. They concern the synthesis, testing in vitro and in vivo and the evaluation of mechanisms of action, of a generation of bio-reductive anticancer drugs that can function as hypoxic cell radiation sensitizers, as differential cytotoxic agents for oxygendeficient cells in tumors and as potentiators of other anticancer drugs. These compounds are based on the principles of "dual function" shown by the lead compound RSU 1069, a 2nitroimidazole containing an aziridine function in the 1- substituted side chain. This compound gives rise to substantial radiation and chemo-sensitization at doses an order of magnitude less than those required for misonidazole. Further, the differential toxicity towards hypoxic cells is extremely high showing the potential of this class of compound for use as anticancer drugs activated bioreductively. The basic rationale for this collaborative program is to synthesize new compounds of this type, examine their effectiveness as radiation sensitizers, chemosensitizers and differential cytotoxic agents for oxygendeficient cells in a variety of cell lines in culture, in multicellular spheroids and in experimental tumors of different types that are already established in the applicants' laboratories. In addition, mechanistic studies will include investigation of structure activity relationships since it has already been shown that chemical modifications of RSU 1069 and similar types of compounds can profoundly affect cytotoxicity both in vitro and in vivo without greatly influencing sensitizing ability. For RSU 1069, the high differential hypoxic cytotoxicity is due to its conversion to a highly reactive bifunctional agent by anaerobic reduction. This leads to an increase in strand breakage and cross- linking in DNA. However, RSU 1069 which is also considerably more toxic than misonidazole to aerobic cells, causes oncogenic transformation in unirradiated C3H 10T1/2 and balb 3T3 cells. An important part of the combined program will be to examine therfore the transforming ability of the new compounds in a structureaimed activity study. This will be aimed at assessing the importance of factors such as electronaffinity, the degree of activation of the aziridinyl group and other monofunctional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiationsensitizing effectiveness.