Michael M. Gottesman, M.D.
Laboratory of Cell Biology
Deputy Director for Intramural Research
Building 37, Room 2108
Bethesda, MD 20892-4255
Success in treatment of some disseminated cancers with chemotherapy has led to intensified efforts to understand why many other cancers are intrinsically resistant to anticancer drugs or become resistant to chemotherapy after many rounds of treatment. Work in the Multidrug Resistance Section has revealed that a major mechanism of resistance of cancer cells to natural product anticancer drugs such as Adriamycin, etoposide, vinblastine, actinomycin D, and Taxol is expression of an energy-dependent drug efflux pump, termed 'P-glycoprotein' (P-gp), or the multidrug transporter. This pump system contributes to drug resistance in about 50 percent of human cancers by preventing accumulation of powerful anticancer drugs in cancer cells. The sequence of the multidrug resistance (MDR1) cDNA, determined in our laboratory, has led to (1) a model of the transporter as a pump with 12 transmembrane domains and two ATP sites, and (2) the discovery of a related family of 48 human ABC transporters involved in a variety of essential transport processes in cells. Polymorphisms in the MDR1 gene, including the ?ilent?polymorphism C3435T (no amino acid change) affect drug resistance and sensitivity to inhibitors, probably by changing mRNA structure and the rate of translation. At least a dozen other ABC transporters may contribute to drug resistance in cancer. Recent work using RT-PCR and microarray expression analysis has indicated that several other ABC transporters may contribute to drug resistance in cultured cancer cells. Studies defining the function and mechanism of action of additional ABC transporters such as ABCB5 are in progress. ABCB5 is expressed in melanomas and pigmented tissues, where it confers low levels of multidrug resistance. While the studies on the mechanism and function of P-gp and related ABC transporters in cultured cancer cells has led to a better understanding of possible mechanisms of multidrug resistance and novel ways to circumvent or target resistance such as the super-sensitivity of P-gp-expressing cells to some drugs, clinical relevance is still unclear. Several ABC transporters (ABCB1, ABCC1 and ABCG2) expressed at the blood-brain barrier limit access of many drugs to the brain.
Ongoing projects in the laboratory are dedicated to ascertaining the clinical relevance of in vitro studies of drug resistance and elucidating other mechanisms of multidrug resistance in cancer cells. Using a sensitive assay (Taqman Low Density Array) to detect mRNA for 380 potential drug resistance genes, we have found that many in vitro cultured cancer cell lines are not faithful replicas of the cancers from which they are derived. For some cancers, such as ovarian cancer and hepatoma, expression of a subset of drug resistance genes predicts response to chemotherapy. In acute myelogenous leukemia, each patient with relapsed, drug-resistant leukemia has a different pattern of expression of drug resistance genes.
A model system for cross-resistance to cisplatin, methotrexate, and nucleotide analogs such as 5-fluorouracil (5-FU) has been developed in which accumulation of drugs in resistant cells is much reduced. These cells show reduced uptake of these compounds because the cell surface molecules responsible for this uptake are reduced in amount owing mainly to a protein trafficking defect, which results in their accumulation in cytoplasmic vesicles. Overexpression of a negative transcriptional regulator, GCF2, turns down expression of RhoA, which in turn disrupts the cytoskeleton to cause the trafficking defect.
Cabral F, Sobel ME, Gottesman MM. CHO mutants resistant to colchicine, colcemid or griseofulvin have an altered beta-tubulin. Cell. 1980;20(1):29-36.
Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, Gottesman MM. Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science. 1986;232(4750):643-5.
Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986;47(3):381-9.
Thorgeirsson SS, Huber BE, Sorrell S, Fojo A, Pastan I, Gottesman MM. Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science. 1987;236(4805):1120-2.
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525-8.