The objective of this project is to investigate three components of the DNA damage and repair process in human colon cancer model systems and patient-derived samples to determine their relation to alkylating agent resistance and to evaluate whether their modulation will improve alkylating agent sensitivity. The alkylating agents to be investigated will include BCNU and melphalan. The model systems to be studied will include a series of cell lines, selected from a bank of over 25 human colon cancer cell lines, to reflect intrinsic and acquired resistance mechanisms for BCNU and melphalan. Tissue samples obtained at surgery and by needle biopsy will be analyzed to define in vivo biochemical patterns associated with alkylating agent resistance and correlations will be made with results obtained in tissue culture. The three components of DNA damage and repair to be investigated include (1) formation and repair of DNA crosslinks and strand breaks; (2) poly(ADP-ribose) and pyridine nucleotide metabolism; and (3) topoisomerase I and II activity. Biochemical studies will be performed to establish the rational basis for modulating these processes. Strategies using modulators in combination with alkylating agents will be tested in tissue culture for their ability to produce the desired biochemical endpoint and/or synergistic chemotherapeutic effects. Regimens producing synergistic interactions will be extended to in vivo trials of human colon cancer xenografts in athymic mice to confirm antitumor selectivity. They will then be developed into clinical trials where further evaluation of biochemistry and modulating effects will be used to optimize therapy of patients with colon cancer.
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