COMBINED EXPRESSION OF MULTIDRUG-RESISTANCE PROTEIN (MRP) AND GLUTATHIONE-S-TRANSFERASE P1-1 (GSTP1-1) IN MCF7 CELLS AND HIGH-LEVEL RESISTANCE TO THE CYTOTOXICITIES OF ETHACRYNIC-ACID BUT NOT OXAZAPHOSPHORINESOR CISPLATIN

We tested the hypothesis that combined increased expression of human g lutathione S-transferase P1-1 (GSTP1-1), an enzyme that catalyzes the conjugation with glutathione of several toxic electrophiles, and the g lutathione-conjugate efflux pump, multidrug resistance protein (MRP), confers high level resistance to the cytotoxicities of anticancer and other drugs. To accomplish this, we developed MCF7 breast carcinoma ce ll derivatives that express high levels of GSTP1-1 and MRP, alone and in combination. Parental MCF7 cells, which express no GSTP1-1 and negl igible MRP, served as control cells. We found that either MRP or GSTP1 -1 alone conferred significant resistance to ethacrynic acid cytotoxic ity. Moreover, combined expression of GSTP1-1 and MRP conferred a high level of resistance to ethacrynic acid that was greater than resistan ce conferred by either protein alone. Increased MRP was also associate d with modest resistance to the oxazaphosphorine compounds mafosfamide , 4-hydroxycyclophosphamide, and 4-hydroperoxycyclophosphamide. Howeve r, coordinated expression of GSTP1-1 with MRP failed to augment this m odest resistance. Similarly, GSTP1-1 had no effect on the sensitivitie s to cisplatin of MCF7 cells regardless of MRP expression. These resul ts establish that coordinated expression of MRP and GSTP1-1 can confer high level resistance to the cytotoxicities of some drugs, including ethacrynic acid, but that such resistance is variable and does not app ly to all toxic drugs that can potentially form glutathione conjugates in either spontaneous or GSTP1-1-catalyzed reactions. (C) 1998 Elsevi er Science Inc.