LACK OF A ROLE FOR MRP1 IN PLATINUM DRUG-RESISTANCE IN HUMAN OVARIAN-CANCER CELL-LINES

The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their var iants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any oi the cell li nes. In addition, we have transfected the MRP1 gene into an intrinsica lly cisplatin-resistant cell line SKOV3, previously shown to have elev ated levels of glutathione (GSH). The MRP1-transfected line SKOV3-S2 w as shown to be cross-resistant to doxorubicin, vincristine and etoposi de but not to paclitaxel, vinblastine and platinum agents, such as cis platin, JM216 [bis-acetato-amwmine-dichloro-cyclohexylamine platinum ( IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II) ]. No cross-resistance to any of the platinum agents was observed in a MRP1-overexpressing human lung cancer cell line with acquired doxorub icin resistance. Reduction of GSH levels (80-90%) by buthionine sulpho ximine (BSO) produced significant potentiation in cisplatin sensitivit y in the parental SKOV3, the vector-alone control SKOV3-puro and the M RP1-transfected line SKOV3-S2, The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4,1-fold) b ut not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV2-puro and the SKOV3-S2 cells, a lthough both these transfected lines accumulated significantly more th an the parental line, Our results suggest that MRP1 does not play a si gnificant role in platinum resistance in the human tumour cell lines i nvestigated in this study.