GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

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Although a large number of tumors can be successfully treated initially with chemotherapy, the development of resistance to drugs is a major limitation. Tumors that are resistant following treatment are often resistant to more than one drug. This multidrug resistance (MDR), at least in some cases, is due to the overexpression of the P- glycoprotein/MDR genes. The MDR genes function as adenosine triphosphate (ATP)-dependent pumps that can extrude a wide variety of hydrophobic compounds from the cell. Although the normal function of the MDR genes is not known, they are part of a superfamily of membrane-bound transport molecules, the ATP-binding cassette (ABC) superfamily. Using molecular cloning techniques we have characterized several MDR-related genes from simple eukaryotic species and bacteria. The complete sequence of a Drosophila melanogaster gene (Mdr50) was determined and the gene was mapped to chromosome 2, band 50. Two genes have been characterized from the yeast, Saccromyces cerevisiae. These genes have been placed onto the genetic map and genetic disruptions of the genes have been obtained. Currently we are testing a number of chemotherapy drugs to see whether increased resistance or sensitivity is controlled by these genes. A MDR- related gene from Escherichia coli has been completely sequenced. This gene, mdl, is the largest gene of this superfamily to date that has been identified in bacteria. Mutations in the gene fail to affect the viability of bacteria, and the potential role of this gene in drug resistance is being examined. If the proteins encoded by these genes can be demonstrated to transport drugs, they may provide a better understanding of the function of MDR genes and the development of MDR. Searches of the DNA sequence data bases have revealed the presence of at least 15 uncharacterized members of the ABC superfamily in the human genome. Probes from two of these genes demonstrate that they are expressed in a tissue-specific manner, and that they map to different chromosomes. Genetic characterization of these genes may reveal a number of functionally important molecules that may be involved in the transport of substances by cells.