GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

对药物的耐药性的发展是一个主要的限制

The development of resistance to drugs is a major limitation to the successful treatment of malignancies with chemotherapy. Multidrug resistance (MDR), defined as tumors that are resistant to more than one drug, is particularly problematic. MDR is partially due to the overexpression of the P-glycoprotein/MDR genes. These genes function as adenosine triphosphate (ATP)-dependent transporters that can extrude a large variety of hydrophobic compounds from the cell. The normal function of the human MDR genes is unknown; however, they are part of a super-family of membrane-bound transport molecules, the ATP-binding cassette (ABC) superfamily. In Escherichia coli at least 25 ABC genes have been identified, whereas in humans only 8 members of the gene superfamily have been described. Human ABC genes are involved in several diseases such as cystic fibrosis and adrenoleuko-dystrophy. In an effort to characterize new human ABC genes, we have screened the expressed sequence tags database and identified several new sequences that may represent ABC genes. To date four clones, containing sequences of the genes that are members of the ABC superfamily, were identified. The four genes display extensive diversity in sequence and expression pattern. In addition, the new genes, mapped using somatic cell hybrid panels and fluorescence in situ hybridization, are located on chromosomes 1, 9 and 10; at locations distinct from previously mapped genes of this superfamily. Expression studies in different tumors are in progress, the ultimate goal being a functional characterization of the described genes. Furthermore, genetic characterization of the ABC genes may reveal a number of functionally important molecules that may be involved in the transport of substances by cells.