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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053340-03
Application #
2095287
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1992-02-01
Project End
1995-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Finch, R A; Liu, M C; Cory, A H et al. (1999) Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone;3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul 39:3-12
Lawrence, T S; Davis, M A; Tang, H Y et al. (1996) Fluorodeoxyuridine-mediated cytotoxicity and radiosensitization require S phase progression. Int J Radiat Biol 70:273-80
Shyam, K; Penketh, P G; Loomis, R H et al. (1996) Antitumor 2-(aminocarbonyl)-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)- hydrazines. J Med Chem 39:796-801
Liu, M C; Lin, T S; Sartorelli, A C (1995) Chemical and biological properties of cytotoxic alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones. Prog Med Chem 32:1-35
Liu, M C; Lin, T S; Penketh, P et al. (1995) Synthesis and antitumor activity of 4- and 5-substituted derivatives of isoquinoline-1-carboxaldehyde thiosemicarbazone. J Med Chem 38:4234-43
Cory, J G; Cory, A H; Rappa, G et al. (1995) Structure-function relationships for a new series of pyridine-2-carboxaldehyde thiosemicarbazones on ribonucleotide reductase activity and tumor cell growth in culture and in vivo. Adv Enzyme Regul 35:55-68
Penketh, P G; Shyam, K; Sartorelli, A C (1994) Studies on the mechanism of decomposition and structural factors affecting the aqueous stability of 1,2-bis(sulfonyl)-1-alkylhydrazines. J Med Chem 37:2912-7
Cory, J G; Cory, A H; Rappa, G et al. (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335-44
Shyam, K; Penketh, P G; Divo, A A et al. (1993) Synthesis and evaluation of 1-acyl-1,2-bis(methylsulfonyl)-2-(2- chloroethyl)hydrazines as antineoplastic agents. J Med Chem 36:3496-502
Wang, Y; Liu, M C; Lin, T S et al. (1992) Synthesis and antitumor activity of 3- and 5-hydroxy-4-methylpyridine-2-carboxaldehyde thiosemicarbazones. J Med Chem 35:3667-71

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