The applicant's recent study indicates that fludarabine inhibits the repair of cisplatin-induced DNA damage in tumor cell lines. Because the two drugs also produce a cytotoxic synergy, the combination (PF; in some patients, with araC, PFA) is now being tested in clinical trials at her institute for patients with refractory chronic lymphocytic leukemia (CLL) or a variant disorder. Using methods established in her laboratory and patients enrolled in the PF protocol, she intend to accomplish these Specific Aims: l. Determine the mechanisms by which fludarabine inhibits DNA repair by separately analyzing fludarab~ne's effects on DNA incision, repair synthesis, and ligation of cisplatin-damaged plasmids in vitro. 2. Correlate the inherent cellular DNA repair capacity and the level of DNA damage with treatment response in leukemia patients who are undergoing PF treatment. The relative effectiveness of the active gene- specific DNA damage and the overall genomic DNA damage in predicting clinical response will be determined. The applicant's immediate objectives are twofold: to elucidate the mechanisms by which fludarabine inhibits DNA excision repair and to evaluate the usefulness of her methods of predicting clinical tumor response. Her longrange goals are to use this inf6rmation to design new therapies for CLL and to develop methods for identifying the patients most likely to benefit from these therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA068137-05
Application #
2895346
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
1995-09-01
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2002-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030