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Human Multidrug-Resistant Cell Lines: Increased mdr 1 Expression Can Precede Gene Amplification
Abstract
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, mdr 1). During colchicine selection resistance is initially accompanied by elevated expression of a 4.5-kilobase mdr 1 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 mdr 1 DNA. Increased expression and amplification of mdr 1 sequences were also found in multidrug-resistant sublines of human leukemia and ovarian carcinoma cells. These results suggest that increased expression of mdr 1 mRNA is a common mechanism for multidrug resistance in human cells. Activation of the mdr 1 gene by mutations or epigenetic changes may precede its amplification during the development of resistance.
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Cited by
Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., & Willingham, M. C. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.21.7735 · Cited by 2,777
Self-citationChen, C.-J., Chin, J. E., Ueda, K., Clark, D. P., Pastan, I., Gottesman, M. M., & Roninson, I. B. (1986) · Cell · doi:10.1016/0092-8674(86)90595-7 · Cited by 1,898
Self-citationExpression of a multidrug-resistance gene in human tumors and tissues.
Fojo, A. T., Ueda, K., Slamon, D. J., Poplack, D. G., Gottesman, M. M., & Pastan, I. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.1.265 · Cited by 1,544
Self-citationAutophagy suppresses tumor progression by limiting chromosomal instability
Mathew, R., Kongara, S., Beaudoin, B., Karp, C. M., Bray, K., Degenhardt, K., Chen, G., Jin, S., & White, E. (2007) · Genes & Development · doi:10.1101/gad.1545107 · Cited by 938
The molecular basis of multidrug resistance in cancer: The early years of P‐glycoprotein research
Gottesman, M. M., & Ling, V. (2006) · FEBS Letters · doi:10.1016/j.febslet.2005.12.060 · Cited by 558
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Metadata
- Authors
- Shen, D.-W., Fojo, A., Chin, J. E., Roninson, I. B., Richert, N., Pastan, I., & Gottesman, M. M.
- Venue
- Science
- Published
- 1986-05-02
- Volume
- 232
- Issue
- 4750
- Pages
- 643-645
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1971950332
- Cited by
- 603
- References
- 0
- FWCI
- 22.79
- Type
- journal article
- Language
- en
- Open access
- closed
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- Shen, D.-W., Fojo, A., Chin, J. E., Roninson, I. B., Richert, N., Pastan, I., & Gottesman, M. M. (1986). Human Multidrug-Resistant Cell Lines: Increased mdr 1 Expression Can Precede Gene Amplification. Science. https://doi.org/10.1126/science.3457471
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