The objectives of the proposed research are to develop therapeutic drug regimens that will have use in the 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 effects responsible for therapeutic activity, (b) exploitation of possible neoplastic cellular sites of vulnerability by chemical modification of existing agents, 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: (1) Development of an alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone with clinical potential by: (a) the synthesis of hydroxy-substituted pyridine and isoquinoline thiosemicarbazones and comparison of their activities against transplanted animal tumors; (b) measurement of their effects on DNA synthesis and ribonucleotide reductase of L1210 leukemia and B16 melanoma; and (c) comparison of the metabolism and metabolic disposition of these agents in normal and tumor-bearing animals. (2) Development of 1-(2-chloroethyl)hydrazines as antitumor agents by: (a) extending the evaluation of the clinical potential of 1-(2-chloroethyl)-1, 2,2-tris(methylsulfonyl)hydrazine; (b) the synthesis of new derivatives of this class, particularly thiol-activated analogs; (c) evaluation of their antineoplastic activity against alkylating agent sensitive and resistant tumors both in culture and in animals; and (d) elucidation of biochemical and pharmacological mechanisms responsible for cytotoxic activity.
Showing the most recent 10 out of 11 publications
