Effect of calcium antagonists on the chemosensitivity of two multidrug-resistant human tumour cell lines which do not overexpress P-glycoprotein.

We have examined the ability of eight compounds to enhance adriamycin (ADM) sensitivity of two human tumour cell lines (a small cell lung cancer cell line, NCI-H69, and a fibrosarcoma cell line, HT1080) and their multidrug-resistant variants. The resistant cell lines (H69AR and HT1080/DR4) do not overexpress P-glycoprotein. Verapamil, nicardipine, perhexiline maleate, chloroquine, tamoxifen, clomiphene, prenylamine and trifluoperazine were tested alone and in combination with ADM for their cytotoxic effects. No major differences in sensitivity between the parent and resistant cell lines were noted when these agents were tested alone, except for HT1080/DR4 cells which exhibited a slight collateral sensitivity to nicardipine and H69AR cells which showed cross-resistance to chloroquine and clomiphene. When the chemosensitisers were combined with ADM no enhanced cytotoxicity of either parent cell line was observed. In HT1080/DR4 cells, verapamil showed only a modest dose-dependent chemosensitising effect while the other compounds had no effect. Verapamil and nicardipine enhanced ADM cytotoxicity in H69AR cells slightly but these effects were not dose-dependent. These results demonstrate that the reversal of drug resistance by verapamil and other calcium antagonists in a dose-dependent fashion is not an invariable property of multidrug-resistant tumour cells.