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

Abstract

Background. 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. Methods. 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. Results. 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. Conclusions. 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.

Distribution and activity of doxorubicin combined with SDZ PSC 833 in mice with P388 and P388/DOX leukaemia

“…The more advanced and pretreated the tumour the greater are the chances it will contain cellular clones with multiple and complex resistance mechanisms. It is therefore not surprising that the results so far with reversing agents in extensively pretreated cancer patients highly resistant to chemotherapy have been disappointing (Rodenburg et al, 1991;Raderer and Scheithauer, 1993;D'Incalci, 1995).…”

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

“…brain [11] and melanoma [12], has sparked interest and elicited a move to understand the multimodal mechanisms of action of this synthetic triphenylethylene [3]. Among the most intriguing properties of tamoxifen, independent of estrogen receptor status, is reversal of multidrug resistance (MDR) [3,13,14]. This has resulted in clinical studies (1/ aimed at exploiting the chemosensitizing properties of tamoxifen [15,16].…”

Multidrug resistance phenotype in leukaemic cells from patients with acute myelocytic leukaemia can be detected with 99Tcm-MIBI

“…In small clinical studies of AML and multiple myeloma, promising results have been reported when resistance modifiers have been added to chemotherapy, and trials are under way to investigate whether this can improve treatment results (Sonneveld et al, 1992;List et al, 1993). Clinical studies in solid tumours are, so far, mostly phase I or contain few patients and are therefore not conclusive (Raderer and Scheithauer, 1993).…”