Ribonucleotide reductase catalzyes the rate-limiting step in the de novo synthesis of 2'-deoxyribonucleoside 5'-triphosphates. Since this is a key metabolic step in DNA synthesis and hence, cell replication, ribonucleotide reductase has been a target for the design of antitumor agents. In the proposed studies, ribonucleotide reductase will be purified from Ehrlich tumor cells and the enzymological properties of the enzyme will be studied in detail. Structural features of nucleotide analogs and other compounds which serve as inhibitors of ribonucleotide reductase will be probed. Antibodies to the two non-identical protein subunits will be prepared and used to quantitate the levels of these two subunits under various metabolic conditions. These conditions will involve the study of the effects of specific ribonucleotide reductase inhibitors or specific DNA polymerase inhibitors on the levels and turnover of the two subunits which are required for enzymatic activity. The mechanisms of drug resistance to ribonucleotide reductase inhibitors will be studied in L1210 cells in terms of levels of subunits, altered subunits with different enzyme properties or altered metabolism or activation of the agent (e.g. deoxyadenosine). These studies will provide a better understanding of ribonucleotide reductase in terms of the control of enzyme activity via the enzyme proteins, sites which are vulnerable for drug-targeted chemotherapy, and mechanisms by which drug resistance involving the ribonucleotide reductase step develop.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA042070-01
Application #
3182872
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1986-04-01
Project End
1991-03-30
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
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, A H; Hertel, L W; Kroin, J S et al. (1993) Effects of 2',2'-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells. Oncol Res 5:59-63
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
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, J G; Cory, A H; Long, S D et al. (1992) Altered steady-state levels of the messenger RNAs for c-myc and p53 in L1210 cell lines resistant to deoxyadenosine. Cancer Res 52:2000-3
Johnson, C E; Hughes, K; Cory, J G (1991) Cell-cycle associated transcriptional regulation of ribonucleotide reductase in L1210 leukemia cells and drug-resistant variants. Cancer Commun 3:341-9
Matsumoto, M; Rey, D A; Cory, J G (1990) Effects of cytosine arabinoside and hydroxyurea on the synthesis of deoxyribonucleotides and DNA replication in L1210 cells. Adv Enzyme Regul 30:47-59
Thompson, D P; Carter, G L; Cory, J G (1989) Changes in messenger RNA levels for the subunits of ribonucleotide reductase during the cell cycle of leukemia L1210 cells. Cancer Commun 1:253-60
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
Carter, G L; Thompson, D P; Cory, J G (1989) Mechanisms of drug resistance to inhibitors directed at the individual subunits of ribonucleotide reductase. Cancer Commun 1:13-20
Chiba, P; Cory, J G (1988) CTP: CMP phosphotransferase activity in L1210 cells. Cancer Biochem Biophys 9:353-8

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