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Assessment of P-Glycoprotein, Glutathione-based Detoxifying Enzymes and O⁶-Alkylguanine-DNA Alkyltransferase as Potential Indicators of Constitutive Drug Resistance in Human Colorectal Tumors¹

Institute for Clinical & Experimental Cancer Research, Tiefenaustrasse 120, 3004 Berne [S. M. S. R., F. J., A. Z.], Medical Oncology, Inselspital, Berne [K. B., M. F., T. C.], Pathology Institute, University of Berne [H-J. A.], Switzerland, and Paterson Institute, Christie Hospital, Manchester, England [G. M.]

Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O⁶-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P 0.0005). Individual patients, however, showed very different patterns, with none, several, or all monitored resistance mechanisms elevated in the tumor. The implications both in the choice of drugs and in the use of resistance modifying agents to improve therapy for the individual patient are discussed.

¹ This research was supported mostly by donations to the Swiss and Bernese Cancer Leagues, and partly by the Cancer Research Campaign (United Kingdom).

Received 8/23/90. Accepted 2/ 4/91.

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