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Molecular Pharmacology

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Research ArticleArticle

Prevention of Fluorodeoxyuridine-Induced Cytotoxicity and DNA Damage in HT29 Colon Carcinoma Cells by Conditional Expression of Wild-Type p53 Phenotype

Leslie A. Parsels, Richard C. Zellars, Tania L. Loney, Joshua D. Parsels, Michael F. Clarke, Audrea K. Merchant, Theodore S. Lawrence and Jonathan Maybaum
Molecular Pharmacology October 1997, 52 (4) 600-605; DOI: https://doi.org/10.1124/mol.52.4.600
Leslie A. Parsels
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Richard C. Zellars
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Tania L. Loney
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Joshua D. Parsels
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Michael F. Clarke
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Audrea K. Merchant
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Theodore S. Lawrence
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Jonathan Maybaum
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Abstract

We have examined the effects of conditionally expressing wild-type p53 activity in HT29 cells on DNA damage and cytotoxicity caused by exposure to fluorodeoxyuridine (FdUrd). Expression of wild-type p53 phenotype for 24 hr before FdUrd treatment provided HT29 cells with virtually complete protection from cytotoxicity caused by this drug. In addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. Temporary expression of wild-type p53 activity in the absence of drug treatment caused some loss of clonogenicity, although the magnitude of this cytotoxic effect was small compared with the level of cell kill obtained by treatment with cytotoxic drugs for similar periods of time, indicating that HT29 cells are not highly sensitive to induction of programmed cell death by wild-type p53. Because these observations conflict with previously suggested models for FdUrd-induced damage to parental DNA, we propose an alternative model to explain how incorporation of uracil into nascent DNA might result in single-strand breaks in the opposite (parental) strand and how these breaks might be converted to the double-strand breaks that produce cell death.

Footnotes

    • Received January 21, 1997.
    • Accepted June 23, 1997.
  • Send reprint requests to: Dr. Jonathan Maybaum, Department of Pharmacology, 4701 Upjohn Center for Clinical Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0504. E-mail: maybaum{at}umich.edu

  • This work was supported by National Institute of Health Grants P01-CA42761 and R01-CA56663 (J.M.), R04-CA53440 (T.S.L.), and Pharmacological Sciences Training Grant 2T32-GM07767, a Predoctoral Fellowship from the University of Michigan Medical School Cancer Research Committee (L.A.P.), and an American Society for Therapeutic Radiation Oncology fellowship (R.C.Z.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (4)
Molecular Pharmacology
Vol. 52, Issue 4
1 Oct 1997
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Research ArticleArticle

Prevention of Fluorodeoxyuridine-Induced Cytotoxicity and DNA Damage in HT29 Colon Carcinoma Cells by Conditional Expression of Wild-Type p53 Phenotype

Leslie A. Parsels, Richard C. Zellars, Tania L. Loney, Joshua D. Parsels, Michael F. Clarke, Audrea K. Merchant, Theodore S. Lawrence and Jonathan Maybaum
Molecular Pharmacology October 1, 1997, 52 (4) 600-605; DOI: https://doi.org/10.1124/mol.52.4.600

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Research ArticleArticle

Prevention of Fluorodeoxyuridine-Induced Cytotoxicity and DNA Damage in HT29 Colon Carcinoma Cells by Conditional Expression of Wild-Type p53 Phenotype

Leslie A. Parsels, Richard C. Zellars, Tania L. Loney, Joshua D. Parsels, Michael F. Clarke, Audrea K. Merchant, Theodore S. Lawrence and Jonathan Maybaum
Molecular Pharmacology October 1, 1997, 52 (4) 600-605; DOI: https://doi.org/10.1124/mol.52.4.600
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