TREATMENT OF ADVANCED COLORECTAL-CANCER WITH DOXORUBICIN COMBINED WITH 2 POTENTIAL MULTIDRUG-RESISTANCE-REVERSING AGENTS - HIGH-DOSE ORAL TAMOXIFEN AND DEXVERAPAMIL

On the basis of the overexpression of the MDR1 gene in human colorecta l cancer, which may constitute a molecular basis for intrinsic drug re sistance that can be reversed, and because of the limited therapeutic value of conventional cytotoxic treatment in this common disease: the present phase II study of P-glycoprotein-directed double modulation wa s initiated. Fifteen patients with measurable metastatic colorectal ca ncer, all of whom were refractory to first-line chemotherapy with 5-fl uorouracil/leukovorin, were entered in this trial. Treatment consisted of 80 mg tamoxifen twice daily on days 1-9, oral dexverapamil every d ay on days 7-9, and 60 mg/m(2) doxorubicin given by intravenous bolus injection on day 8. Courses were repeated every 4 weeks. After a media n of three (between one and six) courses, none of the 14 evaluable pat ients had objective response, and 4 had stable disease, Adverse reacti ons consisted mainly of myelosuppression (WHO grade IV granulocytopeni a was noted in 40%), and mild and reversible dexverapamil-related card iovascular side-effects, specifically hypotension (47%). Our results s uggest that, despite the histological demonstration of high levels of P-glycoprotein in colorectal cancer and administration of two potentia lly synergistic chemosensitizers, we were unsuccessful in circumventin g its primary resistance to chemotherapy.