Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer

Abstract

Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P less than .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine- Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.

Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line

“…It has been shown that a number of small, frequently lipophilic cations, as shown by Zamora et al (1988), are able to reverse in vitro the resistance to anthracyclines, Vinca alkaloids, and other natural products (for review, see Ford and Hait, 1990). Indeed, several of these compounds are able to improve the efficacy of anti-cancer drugs in patients with resistant disease (Salmon et al, 1991;Sonneveld et al, 1992). This confirms the clinical relevance of multidrug resistance, already assessed by the finding that MDRl -gene (P-glycoprotein) over-expression frequently occurred in refractory acute leukemias (Marie et al, 1991) and some solid tumors (Goldstein et al, 1989).…”

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia

“…Recently, phase I/II clinical trials have evaluated the possibility of circumventing MDR 1 efflux function by adding noncytotoxic agents such as cyclosporin A or verapamil (List et al, 1994;Salmon et al, 1991;Sonneveld et al, 1992). Second-generation reversal agents which lack major immunosuppressive or cardiovascular side-effects are now becoming available.…”

Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

“…Pgp is a protein that transports many structurally unrelated substrate drugs. This property has been used to saturate Pgp with non-cytotoxic agents in order to prevent efflux of active drugs, such as verapamil, cyclosporin A and others (Tsuruo et al, 1983;Dalton et al, 1989;Salmon et al, 1991;Solary et al, 1991;Sonneveld et al, 1994). Reversal of MDR by blocking Pgp can be demonstrated in vitro by a functional drug efflux assay and by clonogenic assays.…”