Colon carcinoma is the second leading cause of cancer death among American adults. While no patients have yet been cured, recent data from both this and other institutions has demonstrated a response rate of 50% in metastatic colon cancer treated with high dose alkylators. It is of clear import to obtain greater understanding of the biochemical mechanisms by which the tumors ultimately elude this therapy. This investigation will examine the role of four candidate resistance genes in mediating the resistance of colon cancer to high dose alkylators. These genes are: mutant ras oncogenes, metallothionein family genes, glutathione transferases, and the mdr 1 gene. In model systems each of these four genes have been associated with resistance to alkylating agents. Transfection of mutant ras oncogenes and metallothionein family genes in selected call lines induce resistance to some alkylating agents. Expression of both glutathione transferases and of the mdr 1 gene correlates with acquisition of alkylator agent resistance in several cell lines. Expression of each of these four genes has been documented in some colon carcinomas. This project will systematically explore the contribution that each of these genes makes to expression in colon cancer of resistance to high dose melphalan, high dose BCNU, or treatment combining either melphalan or BCNU with an agent to sensitize tumors to these alkylators. This project will define whether expression in colon cancer of these four genes correlates with either naive resistance or acquired resistance to melphalan and BCNU. This project will further use gene transfer technology to examine whether expression of these genes in colon cancer confers resistance to melphalan or BCNU. Lastly, this project will identify colon carcinomas in which melphalan and BCNU resistance are mediated by novel mechanisms other than those encoded by these four genes. These studies will be done in a unique laboratory model of colon carcinoma call lines and nude mouse xenografts which exhibit alkylator sensitivity and naive and acquired alkylator resistance. These studies will be correlated with findings in tissues from patients participating in a clinical study of high dose alkylator treatment for metastatic colon cancer. This investigation will thus determine the applicability of observations in model systems to the important clinical problem of how to improve the responsiveness of human colon carcinoma to treatment with high dose alkylators.
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