The Atpbinding Cassette Superfamily Of Drug Transporters

The ATP-binding cassette (ABC) superfamily includes P-glycoprotein (MDR1, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), canalicular multiorganic anion transporter (cMOAT, ABCC2), and breast cancer resistance protein/mitoxantrone resistance protein (BCRP/MXR, ABCG2). These transporters play an important role in drug distribution and elimination, being expressed in the lower intestinal tract, liver, kidney, and blood-brain. The transporters also play an important role in resistance to structurally unrelated anticancer drugs, including mitoxantrone, anthracyclines, paclitaxel, SN-38, vinca alkaloids, and epipodophyllotoxins (92,93). Many tumors overexpress more than one ABC transporter; however, ABCB1 is the most important member of the family, and drug resistance characterized by its overexpression is associated with altered distribution and reduced drug levels intracellularly (94). The ABCB1 gene is polymorphic, and several SNPs have been identified, including A61G, G1199A, C1236T, and G2677T; the C3435T variant is associated with a lower expression of MDR1 (ABCB1) in homozygous TT patients with respect to the CC genotype (95,96). Clinical studies on the effect of the C3435T SNP on MDR1 function have produced discrepant results and led to the suggestion that haplotype analysis of the gene should be considered instead of simple SNP detection (97). Expression levels of BCRP, LRP, MRP1, MRP2, and MDR1 in breast cancers responding to anthracycline-based chemotherapy were markedly lower when compared with nonresponding tumors. Furthermore, high expression of MDR1 was found to be significantly associated with a poor progression-free survival (98). In addition to this, MDR1 expression correlated with shorter progression-free survival in locally advanced bladder cancer. MRP1 expression significantly predicted for higher likelihood of response and bladder preservation following neoadjuvant chemotherapy and high lung resistance-related protein/major vault protein (LRP/MVP) expression was associated with worse response to neoadjuvant chemotherapy and a decrease in the probability of bladder preservation (99). Moreover, patients with LRP-positive metastatic tes-ticular germ-cell tumors had significantly shorter progression-free and overall survival than LRP-negative patients, suggesting that LRP upregulation at the time of diagnosis is associated with an adverse clinical outcome (100). Finally, LRP expression correlated inversely with response to platinum-based chemotherapy in NSCLC (response rates, 33% and 100% for patients with LRP-positive and LRP-negative tumors, respectively) (101).

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