Mutations or loss of expression of DNA mismatch repair (MMR) genes especially MLH1, MSH2 and PMS2) have been found with an increasing frequency in many types of sporadic human colon cancers, along with the causal relationship previously observed with hereditary nonpolyposis colorectal cancers (HNPCC). MMR-deficient human tumor cells have demonstrated resistance to many different types of clinically active chemotherapy drugs, pointing out the potential need for new treatment approaches for MMR-deficient tumors. The observed drug resistance in MMR-deficient cells may be attributed to """"""""damage tolerance"""""""", an inability of the cell to detect or respond to chemotherapy-induced DNA damage. The purine analog, 6-thioguanine (6-TG) is used experimentally to define the """"""""damage tolerant"""""""" phenotype of MMR-deficient cells. Recent data from our laboratory suggest that MLH1-, MMR-deficient cells have reduced clonogenic survival and reduced G2/M arrest following ionizing radiation (IR) exposures. Additionally, we found that MLH1- (and, preliminarily, MSH2-), MMR-deficient cells show """"""""damage tolerance"""""""" following exposures to the halogenated thymidine (dThd) analogs, bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd); resulting in greater than 2-3 fold higher levels of incorporated drug into DNA, compared to genetically-matched wild type (MMRT) tumor cells. Consequently, we found that treatment with BrdUrd or IdUrd prior to IR resulted in a significant enhancement in IR-induced cytotoxicity (radiosensitization) in MLH1-, MMR-deficient cells, but not in the matched MLH1+, MMR-proficient tumor cells. We hypothesize that it may be possible to develop treatment strategies to target MMR-deficient human cancers using halogenated thymidine analog-mediated radiosensitization. These preclinical studies will be the first step in the development of a Phase I/Il tumor-specific treatment strategy to target MMR-deficient tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA084578-01
Application #
6052024
Study Section
Special Emphasis Panel (ZRG1-CPA (06))
Program Officer
Stone, Helen B
Project Start
2000-01-25
Project End
2003-12-31
Budget Start
2000-01-25
Budget End
2000-12-31
Support Year
1
Fiscal Year
2000
Total Cost
$212,326
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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