Expression of multidrug-resistance-associated protein (MRP) and chemosensitivity in human gastric cancer.

Abstract

Evidence has accumulated that, in addition to the MDR1 gene-coded P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) also mediates the multidrug resistance (MDR) of various human tumors. In the case of gastric cancer, there is little or no involvement of P-glycoprotein, and the mechanisms of MDR remain to be understood. To search for a possible relationship between expression of MRP and sensitivity to anti-cancer agents in gastric cancer, 4 gastric cancer cell lines, 43 human gastric carcinomas and 17 adjacent normal gastric tissue samples were analyzed. Expression of MRP mRNA was evaluated using reverse transcription PCR (RT-PCR) and Southern hybridization. Sensitivity of the test samples to the anti-cancer drugs cisplatin (CDDP), doxorubicin (DXR) and etoposide (VP-16) was examined using the MTT¿3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl [2H]-tetrazolium bromide¿ assay. Immunohistochemical staining with the use of the MRP antibody (MRPr1) was done to confirm the findings regarding the expression of mRNA levels. The MRP expression evaluated with RT-PCR and Southern hybridization as well as with immunohistochemical staining revealed that 23 of 43 gastric-cancer tissues (53.5%), 15 of 17 normal gastric tissues (88%) and 3 of 4 gastric-cancer cell lines (75%) were positive. The MTT assay showed that DXR was significantly more sensitive (p < 0.01) in gastric carcinoma tissues lacking MRP expression than in those with positive expression. The same tendency was seen with the other agents used. Of the cell lines, one which showed no MRP expression also had a higher sensitivity to CDDP, DXR and VP-16 than the other positive cases. These results show that MRP expression is involved in MDR of human gastric cancer and is inversely related to the chemosensitivity of tumor cells against some anticancer drugs.