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Science 2 May 1986:
Vol. 232. no. 4750, pp. 643 - 645
DOI: 10.1126/science.3457471
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Articles

Science, Vol 232, Issue 4750, 643-645
Copyright © 1986 by American Association for the Advancement of Science

articles

Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification

DW Shen, A Fojo, JE Chin, IB Roninson, N Richert, I Pastan, and MM Gottesman

The development of simultaneous resistance to multiple structurally unrelated drugs is a major impediment to cancer chemotherapy. Multidrug resistance in human KB carcinoma cells selected in colchicine, vinblastine, or Adriamycin is associated with amplification of specific DNA sequences (the multidrug resistance locus, mdr1). During colchicine selection resistance is initially accompanied by elevated expression of a 4.5-kilobase mdr1 messenger RNA (mRNA) without amplification of the corresponding genomic sequences. During selection for increased levels of resistance, expression of this mRNA is increased simultaneously with amplification of mdr1 DNA. Increased expression and amplification of mdr1 sequences were also found in multidrug-resistant sublines of human leukemia and ovarian carcinoma cells. These results suggest that increased expression of mdr1 mRNA is a common mechanism for multidrug resistance in human cells. Activation of the mdr1 gene by mutations or epigenetic changes may precede its amplification during the development of resistance.


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