Development of an MDR-1 Resistance-Reversal Assay

Currently, assays for MDR-1 expression are for research purposes only. This study will determine if measurement of MDR-1 expression by flow cytometry can be performed as a routine clinical assay, and if such an assay can predict the clinical response of patients treated with Taxol for ovarian cancer. Furthermore, the value of testing in vitro resistance- reversal by verapamil and cyclosporin analogue will also be assessed. Phase I will evaluate the feasibility of acquiring and testing the tissues and obtain initial data on patient outcome. Phase II will evaluate a large number of patients to test the statistical significance of these assays. Expression of MDR-1 by intrinsically drug resistant tumors such as renal, colon, adrenal, and pancreatic cancers indicates the broad spectrum of tumor types where drug resistance may be related in part to a specific drug-afflux mechanism. The notion that MDR-1 expression is clinically related to treatment failure has been supported by Salmon's group at the University of Arizona; recent clinical trials indicated that MDR reversal in refractory patients expressing MDR-1 could improve patient outcome. Both verapamil and cyclosporin have been found to sensitize patients to doxorubicin and vincristine. However, use of these reversing agents is associated with systemic toxicity, and not all drug resistant patients expressing MDR-1 will benefit from verapamil or cyclosporin treatment. To fully realize the clinical utility of MDR-resistance reversal, it will be necessary to study the relationship between MDR-1 expression and patient outcome for a large number of patients. This study will focus on the development of a clinical assay to evaluate patient tumors for MDR-1 expression, in vitro drug resistance, and resistance reversal by verapamil and cyclosporin analogue. Patients to be evaluated in Phase I are part of GOG-118 and have untreated stage 3 or 4 epithelial ovarian cancer. They will be treated on protocol GOG-132 with cisplatin, taxol or taxol plus cisplatin. Each patient specimen will be tested for MDR-1 expression by flow cytometry and histochemistry. In vitro response to cisplatin, Taxol, or the combination, in the presence and absence of verapamil and cyclosporin analogue will be determined by the Kern tritiated thymidine incorporation assay. Patient outcome will be determined at second look laparotomy and correlated to the assay results.