GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

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Resistance of tumors to several drugs (Multidrug Resistance, MDR) is a major limitation of cancer chemotherapy. In some tumors MDR is due to the overexpression of the P-glycoprotein/(PGP)MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of a family of adenosine triphosphate (ATP)-dependent transporters and have been shown to cause the efflux of a large variety of compounds from the cell. The gene family is known as the ATP-binding cassette (ABC) family, and its members transport multiple diverse compounds across the membranes of cells and tissues. Human ABC genes are involved in a number of diseases including cystic fibrosis, adrenoleuko-dystrophy, and familial persistent hyperinsulinemic hypoglycemia. To identify new genes involved in multidrug resistance we have characterized 21 new human ABC genes. The genetic location of each of these genes as well as their expression pattern has been determined. One of these genes, MRP3, is expressed predominantly in the liver. The expression of this gene in a panel of cells used for the screening of 40,000 potential chemotherapeutic families has been assessed. This data provides information on the nature of molecules transported by MRP3. We have cloned a Caenorhabditis elegans homolog of the human MRP gene mrp-1 and determined the expression of the gene in the cells of this nematode. The mrp-1 gene is expressed in several secretory cells in the animal, consistent with the gene playing a role in the removal of toxic compounds. Genetic disruption of the mrp-1 gene demonstrates that it is essential for removal of cadmium, a function of the human MRP gene. This animal model of MRP function should be useful in further understanding the mechanism of action of this drug and heavy metal transporters.