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Implications for Therapy of Drug-metabolizing Enzymes in Human Colon Cancer¹

Departments of Medicine [K. M-I., N. H., G. B.], Oncology [G. B.], and Pathology [M-S. T.], The Montreal General Hospital and McGill University, Montreal, Quebec, Canada H3G 1A4

Human colonic tissue is exposed to a variety of toxic chemicals and potential carcinogens in the diet and the intestinal microenvironment. Colonic adenocarcinoma is commonly resistant to the cytotoxic effects of most chemotherapeutic drugs. We have examined drug metabolic and detoxification pathways in clinical specimens of colon carcinoma and normal adjacent mucosa from 17 patients. All elements of xenobiotic metabolism examined are present in these tissues, including cytochrome P-450-dependent enzymes, glutathione, and glutathione-utilizing enzymes. In comparison of tumor tissue to its respective normal mucosa specific alterations in the pathways affecting a number of chemotherapeutic agents were detected, including significantly higher glutathione, glutathione peroxidase, and anionic glutathione-S-transferase activity. These and other alterations found here could be the target of therapeutic maneuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.

¹ This research was supported by grants from The National Cancer Institute of Canada.

² Recipient of a fellowship from the Cancer Research Society, Inc.

³ Scholar of the Medical Research Council of Canada.

⁴ To whom requests for reprints should be addressed, at The Montreal General Hospital, 1650 Cedar Avenue, Room 960, U.S.C., Montreal, Quebec, Canada H3G 1A4.

Received 12/29/88. Revised 5/ 1/89. Accepted 5/26/89.

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