Relating Gene Expression to Multidrug Resistance

Cancer researchers investigating the problem of multidrug resistance--development of resistance to anticancer drugs by tumor cells--have profiled the mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines to screen for anticancer activity and to relate gene expression to the effectiveness of anticancer drugs.

The ATP (adenotriphosphate)-binding cassette (ABC) genes represent the largest family of transmembrane proteins. These proteins bind ATP and use the energy to drive the transport of various molecules across all cell membranes. Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding domains.

Investigators at the U.S. National Cancer Institute (Bethesda, MD, USA; www.nci.nih.gov) used real-time polymerase chain reaction (RT-PCR) technology to detect and quantify the expression of 48 ABC transporter genes in 60 diverse cancer cell lines. The expression of more than 68,500 genes was correlated with the growth inhibitory profiles of 1,429 candidate anticancer drugs.

Results published in the August 24, 2004, issue of Cancer Cell revealed 131 strongly inverse-correlated pairs, where cellular ABC gene expression was strongly correlated with decreased sensitivity to the drug. An unexpected finding was that expression of some ABC transporters, most notably MDR1, caused an increase in sensitivity to some drugs.

Senior author Dr. Michael Gottesman, chief of the laboratory of cell biology at NCI, said, "These results indicate that some of the ABC transporters whose function remains unknown can influence the response of cells to cancer treatment.”

The investigators recommended that research continue to identify other compounds that interact in this way with MDR1 and other ABC transporters to increase sensitivity to chemotherapeutic agents.




Related Links:
U.S.National Cancer Institute