Patients with advanced colo-rectal cancer respond to high dose chemotherapy with alkylating agents in sufficient numbers to provide the basis for cautious optimism that this disease can be cured with biochemical modulation of high dose chemotherapy and autologous bone marrow transplantation. We plan to define the biochemical mechanisms present in colon cancer that limit the antitumor effect of the alkylating agents Melphalan and BCNU and determine how these processes can be modulated to improve the therapy of this disease. A bank of human colon cancer cell lines will be used as models of intrinsic and acquired resistance to Melphalan and BCNU. Resistance pathways will be identified and characterized. Strategies will be developed to overcome resistance patterns primarily associated with the DNA repair pathways and Cellular protective mechanisms including glutathione transferase, thiol metabolism, O(6) alkylguanine alkyltransferase, DNA excision and cross link repair, and poly(ADP-ribose) and pyridine nucleotide metabolism. Molecular Biology studies will be performed to determine the contribution of genes for multidrug resistance, glutathione transferase, metalothione and ras activation to the alkylating agent resistant phenotype. Biochemical modulation protocols developed on the basis of these studies will be tested in vitro in tissue culture and in vivo using a xenograft model of human colon cancer in athymic mice. These studies will provide the rational basis to develop, optimize and test strategies to defeat drug resistance mechanisms. Clinical trials employing biochemical modulators with high dose chemotherapy and autologous bone marrow transplantation will be developed and tested in patients with colon cancer.
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