Abstract

The objective is to participate in the design and testing of new antifolates for use in cancer chemotherapy based on knowledge of folate metabolism. The interaction of folate coenzymes and antimetabolites with folate enzymes of known or potential relevance to cancer chemotherapy will be studied. The program will center on three major areas: 1) Development of an in vitro enzyme system designed to test current hypotheses concerning the interaction of the three enzymes of the thymidylate cycle, dihydrofolate reductase, thymidylate synthase and serine hydroxymethyltransferase.-The central question addressed is: What is the effect of simultaneous inhibition of two of the three enzymes of the cycle on net dTMP formation? Current hypotheses predict antagonism. Our results with bacterial growth studies show that synergistic inhibition can be obtained. 2) Interaction of polyglutamyl 1 inhibitors and coenzymes with folate enzymes.-Polyglutamyl derivatives of folates and of folate antagonists can have a much higher affinity for folate enzymes than the monoglutamate forms. We will study polyglutamate forms of methotrexate, 10-deazaaminopterin, 10-ethyl-10-deazaaminopterin and 5,8-dideaza-10-propargylfolate. The last two compounds named are inhibitors of dihydrofolate reductase and thymidylate synthase respectively and both are in clinical trial. The enzymes to be studied are those mentioned in 1) plus the transformylating enzymes of purine biosynthesis. The enzymes will be derived from cultured human cells, L1210 cells and bacteria. 3) Evaluation of new antifolates synthesized in the laboratories by microbiological assay and enzyme inhibition. Additional studies include: 1) Studies on the metabolism of the natural diastereomer of 5-formyletrahydrofolate in human colon carcinoma xenografts with particular attention to the enhanced antitumor effect when combined with fluorouracil. 2) Studies on the inhibition of dihydrofolate reductase from methotrexate-resistant human squamous cells. 3) Studies on the anti-tumor activity of diastereomers of 5-methyltetrahydrohomofolate. and 4) Studies on the inhibition of thymidylate synthase by combinations of pyrimidine antagonists and folylpolyglutamate analogs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA010914-20
Application #
3163390
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1978-01-01
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
20
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111

  Publications

Hwang, Eung-Soo; Zhang, Zhigang; Cai, Haobin et al. (2009) Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53-dependent transactivation by a mechanism different from that of IE2-86 protein. J Virol 83:12388-98
Gangjee, Aleem; Zeng, Yibin; Talreja, Tina et al. (2007) Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as antifolates. J Med Chem 50:3046-53
Gangjee, Aleem; Yang, Jie; McGuire, John J et al. (2006) Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates. Bioorg Med Chem 14:8590-8
Gangjee, Aleem; Jain, Hiteshkumar D; Kisliuk, Roy L (2005) Novel 2-amino-4-oxo-5-arylthio-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. Bioorg Med Chem Lett 15:2225-30
Gangjee, Aleem; Lin, Xin; Kisliuk, Roy L et al. (2005) Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofol J Med Chem 48:7215-22
Gangjee, Aleem; Zeng, Yibin; Ihnat, Michael et al. (2005) Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity. Bioorg Med Chem 13:5475-91
Gangjee, Aleem; Jain, Hiteshkumar D; McGuire, John J et al. (2004) Benzoyl ring halogenated classical 2-amino-6-methyl-3,4-dihydro-4-oxo-5-substituted thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine antifolates as inhibitors of thymidylate synthase and as antitumor agents. J Med Chem 47:6730-9
Gangjee, Aleem; Zeng, Yibin; McGuire, John J et al. (2004) Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem 47:6893-901
Kisliuk, R L (2003) Deaza analogs of folic acid as antitumor agents. Curr Pharm Des 9:2615-25
Gangjee, Aleem; Yu, Jianming; Kisliuk, Roy L et al. (2003) Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and J Med Chem 46:591-600

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