Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of 2'-deoxyribonucleoside 5'-triphosphates. As such, it represents a critical step in DNA replication and has been a target for the design of antitumor agents. A unique aspect of this enzyme is that it consists of two non-identical protein subunits which can be specifically and independently inhibited. Previous studies established that combinations of ribonucleotide reductase inhibitors, directed at each of the subunits, yielded synergistic inhibition of L1210 cell growth in culture and synergistic cytotoxicity of L1210 cells. It will be the specific aims of this project: to establish the biochemical basis for the synergistic effects induced by the combinations of ribonucleotide reductase; to study the subunit specificity of the reductase inhibitors of the N-hydroxy-N'-aminoguanidine and polyhydroxybenzene series; to study additional combinations of reductase inhibitors which include the N-hydroxy-N'-aminoguanidine and polyhydroxybenzene derivatives; to study the effects of combinations of ribonucleotide reductase inhibitors of L1210 cell growth in vivo; and to determine if there is selective toxicity between the tumor cells and host tissues for these combinations of ribonucleotide reductase inhibitors. The overall goal of this project is to establish combination chemotherapy directed at multiple sites of the same enzyme as an appropriate approach for the treatment of human tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027398-09
Application #
3167599
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1979-09-30
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Cory, J G; Cory, A H; Raber, N K et al. (1993) Structural aspects of N-hydroxy-N'-aminoguanidine derivatives as inhibitors of L1210 cell growth and ribonucleotide reductase activity. Adv Enzyme Regul 33:129-40
Cory, J G; Downes, D L; Ng, C Y et al. (1992) 5-hexyl-2'-deoxyuridine inhibition of nucleoside transport in L1210 cells. Oncol Res 4:175-9
Carter, G L; Cory, J G (1992) Factors affecting the mRNA levels for the non-heme iron and effector-binding subunits of ribonucleotide reductase. Adv Enzyme Regul 32:227-40
Cory, A H; Owen, T C; Barltrop, J A et al. (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3:207-12
Tihan, T; Elford, H L; Cory, J G (1991) Studies on the mechanisms of inhibition of L1210 cell growth by 3,4-dihydroxybenzohydroxamic acid and 3,4-dihydroxybenzamidoxime. Adv Enzyme Regul 31:71-83
Matsumoto, M; Tihan, T; Cory, J G (1990) Effect of ribonucleotide reductase inhibitors on the growth of human colon carcinoma HT-29 cells in culture. Cancer Chemother Pharmacol 26:323-9
Matsumoto, M; Weckbecker, G; Cory, J G (1990) Antineoplastic effect of the combination of 2,3-dihydro-1H-pyrazole[2,3a]imidazole plus deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine in mice with L1210 leukemia cells. Cancer Commun 2:1-6
Cory, J G; Halley, M C; Jeney, A et al. (1990) 5-Hexyl-2'-deoxyuridine blocks the cytotoxic effects of 5-fluorodeoxyuridine or deoxyadenosine in leukemia L1210 cells in culture. Cancer Res 50:4552-6
Weckbecker, G; Cory, J G (1989) Metabolic activation of 2,6-diaminopurine and 2,6-diaminopurine-2'-deoxyriboside to antitumor agents. Adv Enzyme Regul 28:125-44
Carter, G L; Cory, J G (1989) Selective resistance of L1210 cell lines to inhibitors directed at the subunits of ribonucleotide reductase. Adv Enzyme Regul 29:123-39

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