Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas

The expression of ATP-binding cassette superfamily transporter genes, such as P-glycoprotein/multidrug resistance (MDR) 1 and MDR protein (MRP) 1, is often upregulated in various tumor types and is involved in responses to so me anticancer chemotherapeutic agents. Five human MRP subfamily members (MR P2-6) with structural similarities to MRP1 have been identified. The relati onships between MRP2-6 mRNA levels and drug resistance are not well underst ood. Data on 35 patients with colorectal cancer were analyzed. Of the ATP-b inding cassette superfamily genes, we asked whether mRNA levels of MDR1, MR P1, MRP2, and MRP3 correlated with drug resistance to anticancer agents. Fo r this analysis, we used quantitative reverse transcription-PCR, and the se nsitivity to anticancer agents in surgically resected colon carcinomas was determined using the in vitro succinate dehydrogenase inhibition test. MDR1 , MRP1, and MRP3 were highly expressed in normal colorectal mucosa, and the relative mRNA levels of MDR1, MRP1, and MRP3 in cancerous tissues compared with noncancerous tissues were decreased or unchanged. By contrast, MRP2 m RNA expression was low in normal colorectal mucosa and specifically increas ed in cancer regions compared with noncancerous regions. Of the anticancer agents prescribed for patients with colorectal cancers, including doxorubic in, mitomycin C, cisplatin, 5-fluorouracil, etoposide, and a camptothecin d erivative, mRNA expression of MRP2 was significantly associated with resist ance to cisplatin. MRP2 may be important for resistance to cisplatin treatm ent in colorectal cancer.