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Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells

Gros, Philippe and Croop, James and Roninson, Igor and Varshavsky, Alexander and Housman, David E. (1986) Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells. Proceedings of the National Academy of Sciences of the United States of America, 83 (2). pp. 337-341. ISSN 0027-8424. PMCID PMC322853. doi:10.1073/pnas.83.2.337.

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The mechanism by which mammalian cells acquire resistance to chemotherapeutic agents has been investigated by using molecular genetic techniques, LZ and C5, two independently derived multidrug-resistant Chinese hamster cell lines, share specific amplified DNA sequences. We demonstrate that commonly amplified DNA sequences reside in a contiguous domain of approximate to 120 kilobases (kb). We report the isolation of this DNA domain in cosmid clones and show that the level of amplification of the domain is correlated with the level of resistance in multidrug-resistant cell lines. The organization of the amplified domain was deduced by a unique approach utilizing in-gel hybridization of cloned DNA with amplified genomic DNA. We show that the entire cloned region is amplified in adriamycin-resistant LZ cells and independently derived, colchicine-resistant C5 cells. A mRNA species of 5 kb is encoded by a gene located within the boundaries of this region. Genomic sequences homologous to the 5-kb mRNA span over 75 kb of the amplified DNA segment. The level of expression of this mRNA in multidrug-resistant cells is correlated with the degree of gene amplification and the degree of drug resistance. Our results strongly suggest that the 5-kb mRNA species plays a role in the mechanism of multidrug resistance common to the LZ and C5 cell lines.

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URLURL TypeDescription CentralArticle
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 1986 by the National Academy of Sciences. Communicated by S. E. Luria, September 23, 1985. We thank Gail-Lenora Statton and Barbara Doran for secretarial assistance. P.G. is a recipient of a fellowship from the Medical Research Council of Canada. J.C. is supported by a National Institutes of Health training grant (5T 32HL07574). This work was supported by grants from the National Institutes of Health to D.E.H. (CA17575) and A.V. (CA33297) and from the Bristol-Myers Corporation. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
Medical Research Council of CanadaUNSPECIFIED
NIH Predoctoral Fellowship5T 32HL07574
Subject Keywords:gene amplification, in-gel hybridization technique, cosmid cloning, adriamycin resistance, coichicine resistance
Issue or Number:2
PubMed Central ID:PMC322853
Record Number:CaltechAUTHORS:GROpnas86
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1398
Deposited By: Tony Diaz
Deposited On:17 Jan 2006
Last Modified:08 Nov 2021 19:10

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