Clinical trials of agents that reverse multidrug resistance. A literature review.

The discovery of the P-170 glycoprotein as a mediator of multidrug resistance (MDR) represents one of the most important research accomplishments in antineoplastic pharmacology during the last decade. Demonstration of P-170 in epithelial tissues, untreated and chemotherapeutically pretreated human malignancies, and identification of various agents capable of reversing resistance in vitro generated enthusiasm for clinical studies throughout the world. The authors provide an overview of the current status of clinical investigations of MDR1 reversing agents in hematologic and solid malignancies. The authors performed an extensive literature search and selected more than 70 articles concerning the potential clinical relevance of P-glycoprotein/MDR1 modulating agents. Information abstracted included type of reverting agent and chemotherapeutic regimen, number of patients, tumor type, histologic proof of P-glycoprotein expression, and objective response rates. Proof of the involvement of MDR1 in clinical drug resistance has been slow to accumulate, primarily because of difficulties in adapting assays of MDR1 expression and in planning appropriate trials. Pilot studies have shown that verapamil, cyclosporine, and other chemosensitizers may reverse resistance in a subset of patients, but significant (cardiovascular) side effects are common. For leukemias, lymphomas, and multiple myeloma, response rates of 60-80% may be achieved with the potential for cure, whereas in solid tumors, only a few patients appear to benefit. Because of predominantly negative results and unanswered fundamental questions regarding the biology of P-glycoprotein, additional clinical trials with less toxic modulators or their combination are appropriate to delineate optimal strategies for MDR1 reversal and to define the spectrum of responsive tumors. Additional attention also must be given to the coexistence of other resistance mechanisms that may offer separate opportunities for modulation.