RESISTANCE TO THE CHEMOSENSITIZER VERAPAMIL IN A MULTI-DRUG-RESISTANT(MDR) HUMAN MULTIPLE-MYELOMA CELL-LINE

Inhibitors of P-glycoprotein (P-gp) or chemosensitizers, such as verap amil, are used to reverse multi-drug resistance (MDR) in cancer patien ts. Clinical studies in patients with myeloma have shown that some pat ients with P-gp-positive cancer cells respond to the chemosensitizing effect of verapamil. However, this response is short-lived and tumor c ells ultimately become resistant to chemosensitizers. To study mechani sms of resistance to chemosensitizers, a human myeloma cell line, 8226 /MDR(10)V, was selected from a P-gp-positive cell line, 8226/Dox(40), in the continuous presence of doxorubicin and verapamil. MDR(10)V cell s are consistently more resistant to MDR drugs than parent cells, Dox( 40) Chemosensitizers, including verapamil and cyclosporin A, were less effective in reversing resistance in MDR(10)V compared with Dox(40) c ells. Verapamil and cyclosporin A were only partially effective in blo cking P-gp drug efflux in MDR(10)V compared to Doxio cells. Despite hi gher resistance to cytotoxic agents, MDR(10)V cells express less P-gp in the plasma membrane than do its parent cells, Dox(40) [H-3]Azidopin e photoaffinity labeling of P-gp and its binding competition with unla beled verapamil showed similar affinity for P-gp between Dox(40) and M DR(10)V cell lines. Non-P-gp-mediated mechanisms of drug resistance, i ncluding over-expression of MRP and alterations in topoisomerase II, w ere not different for MDR(10)V cells compared with Dox(40) cells. (C) 1996 Wiley-Liss, Inc.