Overexpression of the P-glycoprotein/multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1) gene is closely associated with the clinical outcome of various malignancies, and it is involved in responses to some anticancer chemotherapeutic agents including doxorubicin. Six human MRP subfamily members (MRP2-7) with structural similarities to MRP1 have been identified. Recently, the relationships between MRP2 and MRP3 expression levels of some cancer cells and drug sensitivity to doxorubicin have been reported, but the relationship between the clinical samples and drug sensitivity remains unclear. We determined the expressions of the MDR1, MRP1, MRP2 and MRP3 gene in bladder cancer during the clinical course and sought to learn whether the expression was correlated with drug responses to doxorubicin. Doxorubicin, used in chemotherapeutic treatment including intravesical and systemic chemotherapy, is an important anticancer agent for the treatment of bladder cancer. We used quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for our study, and the sensitivity to doxorubicin in bladder cancer was determined using the in vitro succinate dehydrogenase inhibition test. Using 47 clinical samples of bladder cancer, we confirmed the significant correlation of MDR1, MRP1 and MRP3 mRNA levels with resistance to doxorubicin. We showed that the expression of MDR1, MRP1, MRP2 and MRP3 in recurrent tumors and residual tumors after chemotherapeutic treatment was higher than that in untreated primary tumors. In particular, the MDR1 expression in residual tumors was 5.7-fold higher than that in untreated primary tumors. © 2002 Wiley-Liss, Inc.
Key words: MDR1; MRP1; MRP2; MRP3; drug resistance; doxorubicin; chemotherapeutic treatment; bladder cancerThe appearance of tumor cells resistant to multiple anticancer agents is a serious obstacle during cancer treatment. Such a multidrug resistance phenotype is often associated with increased expression of 2 representative adenosine triphosphate (ATP) binding cassette (ABC) superfamily proteins, P-glycoprotein (P-gp) and the multidrug resistance protein 1(MRP1). 1,2 P-gp and MRP1 participate in drug resistance against a wide variety of anticancer agents, including vinka alkaloids (vincristine, vinblastin), anthracyclines (doxorubicin, daunorubicin). 3 Overexpression of P-gp and MRP1 has been found in human bladder cancer cells selected by drug resistance against doxorubicin. 4,5 In patients with bladder cancers, the expression of P-gp and MRP1 often increased after chemoradiotherapeutic treatment. 6,7 In addition to multidrug resistance (MDR) 1 and MRP1, 6 human MRP subfamily members (MRP2-7) that show structural similarity to MRP1 have been identified. 8 -10 Of these MRP family genes, MRP2, known as the canalicular multispecific organic anion transporter, appears to mediate the ATP-dependent transport of various hydrophobic anionic compounds, including doxorubicin and methotrexate in liver canalicular membranes and other tissues. 11,12 The compl...