CHEMOSENSITIZATION BY VERAPAMIL AND CYCLOSPORINE-A IN MOUSE-TUMOR CELLS EXPRESSING DIFFERENT LEVELS OF P-GLYCOPROTEIN AND CP22 (SORCIN)

The relationships between resistance to adriamycin, vincristine, colchicine and etopside, expression of P-glycoprotein and CP22 (sorcin), and resistance modification by verapamil and cyclosporin A have been studied in a panel of multidrug-resistant (MDR) mouse tumour cell lines. Whereas there was a generally good correlation between the degree of resistance and the amount of P-glycoprotein, no relationship between resistance and CP22 expression was seen. At 3. 3 μM verapamil, the sensitisation of the MDR cell lines was no greater than that of the parent line. At 6. 6 μM verapamil, however, sensitisation of the MDR lines generally exceeded that of the parent line, although the line CR 2. 0, expressing very high levels of P-glycoprotein was an exception. Little sensitisation to etoposide was seen in any of the lines. When cyclosporin A was used as the sensitiser at either 2. 1 or 4. 2 μM, there was a greater effect in lines expressing moderate to high levels of P-glycoprotein than in the parent line, although this tendency was less for adriamycin than for the other cytotoxics. Sensitisation to etoposide was much greater with cyclosporin A than with verapamil. At low levels (< 1 μM) of CsA, however, sensitisation to colchicine was greater in the parent line than in cell line CR 2. 0. These studies indicate that chemosensitisation by verapamil and cyclosporin A is extremely complex, depending upon sensitiser dose, the particular cytotoxic and the cell line. At low doses of the sensitisers, the sensitisation may be greater in lines expressing low levels of P-glycoprotein than in lines showing high levels. © The MacMillan Press Ltd., 1990.