REGULATION OF MULTIDRUG RESISTANCE GENE EXPRESSION

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Chemotherapy has been widely and successfully employed for the treatment of various types of cancer. Unfortunately, many forms of cancer are still refractory to chemotherapy, and others that initially respond favorably later become drug resistant. The emergence of drug resistance encountered in cancer chemotherapy poses a major obstacle to the success of clinical treatment of human malignancies, and remains one of the important unsolved problems. The primary objective of this research is to elucidate the mechanisms by which MDR1 gene expression is regulated during the progression of human malignancies. The genesis of multidrug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which encodes a plasma membrane energy-dependent efflux pump termed, P-glycoprotein (or multidrug transporter), which confers cross-resistance to multiple hydrophobic natural product cytotoxic drugs. Expression of the multidrug-resistance gene occasionally occurs de novo in human cancers in the absence of obvious selective pressure. We have recently shown that the human MDR1 gene promoter is a target for the c-Ha-RAS-1 oncogene and the p53 tumor suppressor gene, two genes associated with tumor progression. the stimulatory effect of c-Ha-RAS-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. The current research proposal attempts to: (1) examine the effects of other oncogenes and tumor suppressor gene, such as c-fos, c-jun, c-myc, and the retinoblastoma gene product, Rb, on the promoter activity of the MDR1 gene; (2) determine and characterize the cis- and trans-acting elements involved in the modulation of the MDR1 promoter by RAS, p53 and Rb; (3) establish a correlation between the expression of MDR1 gene and tumor progression, by developing a tissue culture model system to study the in vivo expression of MDR1 gene after stable transfer of RAS, or either wild-type or mutant p53 and Rb genes; (4) determine the cell type- specific expression and activation of the MDR1 gene promoter by p53 and Rb, an their mechanisms of activation. These results could have significant implications on the activation of the MDR1 gene during tumor progression associated with genetic alterations in RAS, p53 and Rb. Information learned from these studies could then be utilized to design more rational approaches to chemotherapy.