The long-term objectives of this application are to better understand the DNA damage mechanisms that influence the response of normal cells and cancer cells to chemotherapy. Thymidylate deprivation is induced by inhibition of thymidylate synthase (TS) and is a therapeutic effect of several classes of antineoplastic drugs, such as 5-fluorouracil and raltitrexed (Tomudex). Inhibition of TS leads to loss of TTP necessary for replication. Thymidylate deprivation leads to cell death, unlike the cytostatic effects associated with other nutritional deficiencies. Despite decades of study, the precise mechanism by which TS inhibition causes death remains unclear. Some cellular responses to TS inhibition include an alteration in deoxynucleotide pools including an increase in dUTP levels, uracil incorporation into DNA, cell cycle arrest during S-phase, and induction of DNA strand breaks, likely at sites of replication. A key unanswered question remains """"""""what is the specific nature of the damage during thymidylate deprivation that results in cell death?"""""""" The hypothesis to be tested in this project is that activation and progression of base excision repair (BER) under conditions of thymidylate deprivation lead to aberrant recombination and, eventually, apoptosis.
The Specific Aims of this project are:
Aim 1 : To determine whether the initiation and progression of BER during thymidylate deprivation contributes to cell death.
Aim 2 : To determine the fate of BER intermediates during thymidylate deprivation.
Aim 3 : To determine whether chromosomal recombination is induced during thymidylate deprivation and to investigate the influence of BER on recombination occurring during thymidylate deprivation. Because BER and recombination normally contribute to genome stability, these questions have an added significance when current cancer therapies can themselves induce DNA damage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA100450-01A2
Application #
6821551
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Okano, Paul
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$261,172
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
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