CHINESE-HAMSTER OVARY CELLS RESISTANT TO OKADAIC ACID EXPRESS A MULTIDRUG-RESISTANT PHENOTYPE

Two Chinese hamster ovary cell clones resistant to okadaic acid (OA) w ere isolated. The OA-resistance was associated with resistance to colc hicine, Vinca alkaloids and inhibitors of DNA topoisomerase (topo) II, Drug accumulation assays showed that the intracellular levels of OA, vinblastine and vincristine, but not the topo II inhibitor etoposide, were significantly lowered in the OA-resistant mutants than in the par ental cells. These results, together with the finding of an increased level of P-glycoprotein (P-gp) in the mutant cells, indicate that the resistances to OA, Vinca alkaloids and colchicine are due to a P-gp-me diated mechanism. Resistance to topo II inhibitors, however, was assoc iated with reduced activity of topo II. Thus, at least two events, ove rexpression of P-gp and reduction of topo II activity, occurred in a s ingle OA-resistant cell line, contributing to expression of the MDR ph enotype. (C) 1994 Academic Press, Inc.