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Research Article Free access | 10.1172/JCI117910

Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen.

M Alvarez, K Paull, A Monks, C Hose, J S Lee, J Weinstein, M Grever, S Bates, and T Fojo

Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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Published May 1, 1995 - More info

Published in Volume 95, Issue 5 on May 1, 1995
J Clin Invest. 1995;95(5):2205–2214. https://doi.org/10.1172/JCI117910.
© 1995 The American Society for Clinical Investigation
Published May 1, 1995 - Version history
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Abstract

Identifying new chemotherapeutic agents and characterizing mechanisms of resistance may improve cancer treatment. The Anticancer Drug Screen of the National Cancer Institute uses 60 cell lines to identify new agents. Expression of mdr-1/P-glycoprotein was measured by quantitative PCR. Expression was detected in 39 cell lines; the highest levels were in renal and colon carcinomas. Expression was also detected in all melanomas and central nervous system tumors, but in only one ovarian carcinoma and one leukemia cell line. Using a modified version of the COMPARE program, a high correlation was found between expression of mdr-1 and cellular resistance to a large number of compounds. Evidence that these compounds are P-glycoprotein substrates includes: (a) enhancement of cytotoxicity by verapamil; (b) demonstration of cross-resistance in a multidrug-resistant cell line, (c) ability to antagonize P-glycoprotein, increasing vinblastine accumulation by decreasing efflux; and (d) inhibition of photoaffinity labeling by azidopine. Identification of many heretofore unrecognized compounds as substrates indicates that P-glycoprotein has a broader substrate specificity than previously recognized. This study confirms the validity of this novel approach and provides the basis for similar studies examining a diverse group of gene products, including other resistance mechanisms, putative drug targets, and genes involved in the cell cycle and apoptosis.

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