The objectives of the proposed research are to develop therapeutic drug regimens that will have use in he treatment of cancer in man on the basis of pharmacological and biochemical information on the mechanism of drug action, with particular emphasis on (a) characterization of the metabolic alterations responsible for cell death following exposure to chemical stress, (b) exploitation of possible neoplastic cellular sites of vulnerability by chemical modification of existing agents having some clinical efficacy, as well as further design and synthesis of new drugs based upon biochemical and pharmacological principles, and (c) the selection, on the basis of metabolic action, of drugs to employ in combination, thereby gaining increased therapeutic efficacy. Research emphasis is being placed upon the following: (a) quinone imides, quinones, chromones and nitro-containing bioreductive alkylating agents with preferential cytotoxicity for hypoxic cells; (b) alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones, in an effort to develop a second generation inhibitor of ribonucleotide reductase with clinical potential; (c) tetramisole derivatives as inhibitors of alkaline phosphohydrolase and the mechanism by which neoplastic cells attain resistance to the 6-thiopurines; (d) development and study of the biochemical mechanism of action of arylsulfonylhydrazones of pyridine N-oxide as anticancer drugs; (e) effects of anticancer agents and other metabolic inhibitors on surface membranes of neoplastic cells stressing the action of 6-thioguanine and 2-deoxy-D-glucose; (f) role of glycosaminoglycans in muring melanoma metastases, and the development of antimetastatic agents; (g) studies on the comparative action of 2'-azido-2'-deoxy-beta-D-arabinofuranosyladenine and arabinosyladenine; and (h) the mechanism by which 6-thioguanine and certain anthracyclines induce the differentiation of leukemic cells.
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