Chemotherapy induces or increases expression of multidrug resistance-associated protein in malignant melanoma cells

Background Human malignant melanoma is notoriously resistant to chemotherap eutic agents. Melanoma-derived cell lines are often markedly chemoresistant , suggesting that cellular mechanisms mediate generation of the multidrug r esistance (MDR) phenotype. This phenotype is often due to P-glycoprotein (P gp) and the MDR-associated protein (MRP), which are drug transporter protei ns associated with resistance to a broad spectrum of lipophilic drugs. Objectives To determine the relationships between the expression of the MDR gene MDR-1 (the product of which is Pgp) or the MRP gene, and clinical che moresistance of malignant melanoma. Methods We examined changes in the expression of MDR-1 and MRP genes at the mRNA level before and after chemotherapy by reverse transcription-polymera se chain reaction (RT-PCR) analysis using formalin-fixed, paraffin-embedded sections of 18 specimens taken from eight melanoma patients, mRNA expressi on of the MDR-1 and MRP gene-specific PCR products was quantitatively deter mined by densitometry and compared with that of an internal standard (beta -actin). Results Five of seven primary melanomas were found to express the MRP gene to a certain extent even before chemotherapy. After first and second course s of chemotherapy, six patients had an increased ratio of MRP mRNA to beta -actin mRNA compared with the prechemotherapy levels in the same patients. None of the cases of melanoma expressed MDR-1. Conclusions These results suggest that a significant mRNA level of MRP gene was intrinsically present in malignant melanoma even before exposure to ch emotherapeutic drugs and increased in its expression after chemotherapy, su ggesting that MRP plays a part in increasing the chemoresistance of maligna nt melanoma during chemotherapy.