Transcriptional regulation of multidrug resistance gene expression

Abstract

A major problem in cancer chemotherapy is resistance of tumors to a variety of structurally diverse drugs [1]. Numerous mechanisms have been described for failure of cancer chemotherapy [2], which generally fall into three classes: increased metabolic capacity via increased gene expression [3]; target protein alteration, for example, topoisomerase II [4]; and altered drug influx and efflux. In the last of these, one of the most investigated mechanisms involves a small, highly conserved gene family, the multidrug resistance (mdr) gene family, that encode a 170-kDa transmembrane transport protein, P-glycoprotein (for review, see [5]). All the available data suggest that P-glycoprotein functions as an energy-dependent transmembrane efflux pump for a number of chemotherapeutic agents and other xenobiotics [6,7]. The mdr gene family consists of two genes, mdr1 and mdr2, in man and nonhuman primates, and three closely related genes, mdr1a, mdr1b, and mdr2, in the mouse, hamster, and rat [5,8]. Transfection of the mdr1 genes indicates that expression of these genes is per se sufficient to confer the mdr phenotype upon drug-sensitive cell lines [9–11]. This is not the case for the mdr2 [12], the function of which remains to be defined [13]. No normal physiologic role has been determined for any of the P-glycoprotein proteins. The polarized manner of P-glycoprotein expression at the apical membranes of a variety of normal tissues strongly suggests a role for P-glycoprotein in normal cellular transport of both endo- and xenobiotics [14]. Also, differential expression of mdr genes in human, rat, mouse, and hamster tissues indicates that tissuespecific transcription factors may regulate the expression of the distinct mdr genes [15–19].