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Molecular Pharmacology

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Research ArticleArticle

Mechanisms of Acquired Resistance to Thymidylate Synthase Inhibitors: The Role of Enzyme Stability

Maria E. Kitchens, Antonia M. Forsthoefel, Karen W. Barbour, H. Trent Spencer and Franklin G. Berger
Molecular Pharmacology November 1999, 56 (5) 1063-1070; DOI: https://doi.org/10.1124/mol.56.5.1063
Maria E. Kitchens
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Antonia M. Forsthoefel
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Karen W. Barbour
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H. Trent Spencer
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Franklin G. Berger
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Abstract

Inhibitors of the enzyme thymidylate synthase (TS), such as the fluoropyrimidines 5-fluorouracil and 5′-fluoro-2′-deoxyuridine (FdUrd) or the antifolates AG337, ZD1694, and BW1843U89, are widely used in the chemotherapy of cancer, particularly cancer of the colon and rectum. Numerous studies have shown that TS gene amplification, leading to mRNA and enzyme overproduction, is a major mechanism of resistance to these inhibitors. In the present work, we have isolated and characterized FdUrd-resistant derivatives of several human colon tumor cell lines. Although gene amplification was commonly observed, the increases in mRNA and enzyme were strikingly discordant. In one drug-resistant line, a deficiency of enzyme relative to mRNA was shown to be caused by expression of a metabolically unstable TS molecule. The reduced half-life of TS in this line was caused by a Pro-to-Leu substitution at residue 303 of the TS polypeptide. The mutant enzyme conferred resistance to FdUrd as well as antifolates in transfected cells. In another FdUrd-resistant line, which had an excess of enzyme relative to mRNA, the TS molecule was more stable than in the parent line. However, no amino acid substitutions were detected in the TS polypeptide from this line, which suggests that the stabilization must be caused by changes in one or more cellular factors that regulate TS degradation. The results indicate that changes in the stability of the TS polypeptide accompany, and even contribute to, acquired resistance to TS inhibitors in colon tumor cells.

Footnotes

    • Received February 2, 1999.
    • Accepted August 13, 1999.
  • Send reprint requests to: Dr. Franklin G. Berger, Department of Biological Sciences, University of South Carolina, Columbia, SC 29208. E-mail: berger{at}biol.sc.edu

  • This work was supported by a grant from the National Institutes of Health (CA 44013). The research reported in this paper was performed in partial fulfillment of the requirements for the degree of Doctor of Philosophy (M.E.K.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Mechanisms of Acquired Resistance to Thymidylate Synthase Inhibitors: The Role of Enzyme Stability

Maria E. Kitchens, Antonia M. Forsthoefel, Karen W. Barbour, H. Trent Spencer and Franklin G. Berger
Molecular Pharmacology November 1, 1999, 56 (5) 1063-1070; DOI: https://doi.org/10.1124/mol.56.5.1063

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Research ArticleArticle

Mechanisms of Acquired Resistance to Thymidylate Synthase Inhibitors: The Role of Enzyme Stability

Maria E. Kitchens, Antonia M. Forsthoefel, Karen W. Barbour, H. Trent Spencer and Franklin G. Berger
Molecular Pharmacology November 1, 1999, 56 (5) 1063-1070; DOI: https://doi.org/10.1124/mol.56.5.1063
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