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IntroductionThe acquisition of a multidrug-resistant (MDR) phenotype in cancer cells is often associated with increased expression of the cellular surface P-glycoprotein (P-gp), which functions as an energy-dependent drug efflux pump, thereby resulting in a decrease of drug concentrations within cells. 1-3 Expression of P-gp in various malignancies might become one of the major obstacles to chemotherapy, especially in hematopoietic malignancies. [4][5][6] Mammalian P-gps are encoded by small families of genes known as linked MDR genes, of which there are 2 known members in humans (PGY1 and PGY3, also known as MDR1 and MDR3, respectively) 3,7-8 and 3 known members in mice (mdr1a, mdr1b, and mdr2). [9][10][11] The transfection of complementary DNA (cDNA) derived from MDR1, mdr1a, and mdr1b confers multidrug resistance, but the transfection of cDNA from MDR3 and mdr2 does not. 9,10,[12][13][14][15][16] The MDR1 gene is expressed in both normal tissues 17 and malignancies. 18,19 It is thus important to understand how P-gp is specifically expressed in cancer cells in order to use P-gp as a diagnostic marker for MDR in human malignancies. Various mechanisms for MDR1 overexpression have been reported in cultured cancer cell lines or tumor samples from clinical patients. Gene amplification units of the MDR1 gene have often been detected in cancer cells selected for their drug resistance to multiple anticancer agents, 20-24 but amplification has not appeared in clinical samples. The MDR1 gene is activated through transcription factors NF-Y 25 and Y-box binding protein (YB-1) 26 in the presence of exogenous stimuli including ultraviolet light, irradiation, and carcinogens. Cellular translocation of YB-1 from cytoplasm to nuclei has been shown to be closely associated with P-gp expression in several cancers. [27][28][29] The alteration of methylation status at CpG sites on MDR1 gene promoters has also been shown to be involved in MDR1 gene expression in cultured cancer cell lines. 22,30 Demethylation at CpG sites on MDR1 gene promoters has also been closely associated with P-gp expression in patients with acute myeloid leukemias. 31 Mickley et al 32 have reported that gene rearrangement at the 5Ј-flanking region of the MDR1 gene was responsible for transcriptional activation of the MDR1 gene in drug-resistant cell lines derived from colon and breast cancers. The authors also showed rearrangement at the 5Ј-flanking region of MDR1 in clinical samples of acute lymphoblastic leukemias. This activation might be induced by read-through transcription from the promoter of a fused, upstream-positioned gene. Determination of the rearranged sequence indicated that the gene rearrangements occurred from homologous recombination between Alu repeats. 33 As an alternative approach to understanding how the initial onset of drug resistance in cancer cells appears during anticancer chemotreatment in vivo, an animal model could be useful to clarify the mechanism of overexpression of MDR genes. Chemotherapeutic Supported by a grant from the Mi...