Enhancement of cytotoxicity of vindesine and cis-platinum for human lung tumours by the use of verapamil in vitro

Abstract

The use of verapamil, a calcium channel antagonist, to circumvent established resistance in human cancer cell lines has been reported for lung (Fetherston et al., 1985) and ovary (Rogan et al., 1984) using adriamycin and the vinca alkaloids. We were interested in its potential use for the enhancement of cytotoxicity of vindesine and cisplatinum in non-small cell cancer of lung (NSCCL). An earlier study (Simmonds et al., 1986) using primary patient material in clonogenic assay has confirmed the overall poor clinical response rates to these drugs reported by Elliott et al. (1984).In this study, 18 lung tumour samples, 17 squamous and 1 adenocarcinoma, were removed at thoracotomy of previously untreated patients and grown in the bilayered agar clonogenic assay system. In brief, samples were mechanically disaggregated with crossed scalpels in Hanks balanced salt solution (HBSS) with penicillin and streptomycin and resulting cell suspensions passed through needles of decreasing gauge to obtain single cells. Tumour cells obtained were suspended in RPM1-1640+10% FBS and aliquots of 106 viable cells were exposed for 1 h at 37°C to concentrations representing 10% of the peak plasma concentration for cis-platinum (0.25 pg ml -1) and vindesine (0.02 pgml-1) (Alberts et al., 1980) Figure 1 shows the response to cis-platinum. All specimens except no. 13 were resistant in vitro when tested alone, the degree of resistance varying from moderate to very marked. Fourteen of the 18 patients demonstrated greater than 70% survival following treatment with this drug. In the presence of verapamil, only one patient, number 8, showed a change to sensitivity from 60% to 36% survival. Patient 13 had sensitivity changed to resistance while samples number 7, 11, 12, 17 and 18 demonstrated increased resistance. A change in the degree of resistance was observed for patients 2, 4, 5, 6, 9, 10, 14, and 15; this was lessened while specimens from patients 1, 3 and 16 were unaffected. Plating efficiencies in every case were sufficiently high for these drug results to be significant (11/18PE>0.03%) and the treatment of cells with verapamil alone produced no cytotoxic effects (figures not shown). Figure 2 shows the response to vindesine. In the absence of verapamil all samples were resistant and 10/18 patients exhibited greater than 70% survival following treatment with this drug. Pronounced changes, however, were observed in vindesine response in the presence of verapamil for 7 samples; patient numbers, 2, 5, 6, 7, 8 and 13 became

Interactions between Calcium Channel Blockers and Non‐Cardiovascular Drugs: Interactions with Anticancer Drugs

“…Similarly the combined use of verapamil and cisplatin in neuroblastoma transplanted to BLAB/c athymic mice leads to a more marked decrease in tum'our growth than cisplatin alone (Ikeda et al 1987). One study using human tumour cells has confirmed the results in experimental animals, as verapamil was observed to enhance cisplatin cytotoxicity in 50% of tumour samples from previously untreated patients with non-small cell lung carcinoma (Simmonds et a/. 1986).…”

Clinically relevant concentrations of verapamil do not enhance the sensitivity of human bone marrow CFU-GM to adriamycin and VP16

“…In the context of enhancement of drug sensitivity this concentration of verapamil is at the lower end of the dose-response curve, but some studies (Yalowich & Ross, 1984;Slater et al, 1986;Supino et al, 1986) do indicate that verapamil may enhance sensitivity to adriamycin and VP16 at concentrations of 1-2pM in vitro. These concentrations of verapamil in vitro have also been reported to enhance tumour cell sensitivity to vinca alkaloids (Tsuruo et al, 1981;Tsuruo et al, 1983a;Simmonds et al, 1986) and daunorubicin (a structural analogue of adriamycin; Slater et al, 1982). In vivo, using animal ascites tumour models, verapamil has been reported to enhance sensitivity to VP16 (Slater et al, 1986), daunorubicin (Slater et al, 1982) and vincristine (Tsuruo et al, 1981).…”

Modulation of Mitoxantrone Cytotoxicity by Verapamil in Human Chronic Myeloid Leukemia Cells

“…29], vinca alkaloids [2], etoposide [25. 26] melphalan [21] and cis-platinum [12,27], These studies were per formed in drug-responsive and nonresponsive tumors of both murine and human origin [9,10,31].…”