Solid neoplasms are known to contain deficient vascular beds and areas of severe vascular insufficiency, and as a result, may develop regions containing hypoxic tumor cells. These malignant cells, which frequently constitute 5 to 30% of the total viable tumor cell population, may form a therapeutically resistant group within solid tumors. Thus, hypoxic neoplastic cells may capable of proliferating and causing tumor regrowth after treatment that produces tumor regression. The overall objectives of this proposal are aimed at exploiting the fact that hypoxic cells in solid tumors exits in an environment conducive to reductive processes by utilizing chemotherapeutic agents that become cytotoxic after reductive activation. Therapeutic drug regiments will be developed that will have use in the treatment of cancer in man based upon pharmacological and biochemical considerations. Specifically, we will (a) study a variety of bioeductive alkylating agents including mitomycin antibiotics, aziridinyl quinone sulfonate and 1-haloalkyl-2-nitroimidazoles; (b) synthesize more efficacious agents of the quinone and nitroimidazole classes and hydroxylamino derivatives of purine and pyrimidine antimetabolites; (c) ascertain the cytotoxic properties of these agents toward neoplastic cell in vitro under both aerobic and hypoxic conditions; (d) determine the potential antineoplastic activity of these materials in animals bearing transplanted murine tumors; (e) study the mechanism of action of these agents in normal and neoplastic cells; and (f) evaluate the effectiveness of combinations of drugs and other modialities employed to eradicate oxygenated and hypoxic cellular compartments of solid tumors.
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