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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

p53-Mediated Regulation of Expression of a Rabbit Liver Carboxylesterase Confers Sensitivity to 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)

Monika Wierdl, Christopher L. Morton, Linda C. Harris, Mary K. Danks, John D. Schuetz and Philip M. Potter
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 699-705; DOI: https://doi.org/10.1124/jpet.102.044149
Monika Wierdl
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Christopher L. Morton
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Linda C. Harris
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Mary K. Danks
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John D. Schuetz
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Philip M. Potter
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Abstract

We have exploited the ability of wild-type (wt) p53 to repress gene expression and produce tumor-selective cytotoxicity using viral-directed enzyme prodrug therapy. Vectors containing either the cytomegalovirus or Rous sarcoma virus promoter regulating transcription of a rabbit liver carboxylesterase (CE) have been constructed. Upon transfection of these plasmids into cells expressing either wt or mutant p53, differential expression of the CE has been observed, resulting in sensitization of the cells expressing the latter protein to the anticancer prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carb- onyloxycamptothecin (CPT-11). Transduction of isogenic cell lines with adenovirus containing CE under control of the Rous sarcoma virus promoter confirmed the decreased sensitization of cells expressing wtp53 to CPT-11. These studies indicate that the inactivation of wtp53 by mutant p53 in human tumor cells may be sufficient enough to generate a therapeutic window for enhanced cytotoxicity with CPT-11.

Footnotes

  • This work was supported in part by National Institutes of Health Grants CA66124, CA76202, CA79763, and ES05851; the Cancer Center Core Grant CA21765, and the American Lebanese Syrian Associated Charities.

  • DOI: 10.1124/jpet.102.044149

  • Abbreviations:
    bp
    base pair(s)
    mdr
    multidrug resistance
    RSV
    Rous sarcoma virus
    SV40
    simian virus 40
    CE
    carboxylesterase
    wtp53
    wild-type p53
    VDEPT
    viral-directed enzyme prodrug therapy
    CMV
    cytomegalovirus
    tdn
    transdominant
    rCE
    rabbit liver carboxylesterase
    kb
    kilobase(s)
    • Received September 6, 2002.
    • Accepted October 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

p53-Mediated Regulation of Expression of a Rabbit Liver Carboxylesterase Confers Sensitivity to 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)

Monika Wierdl, Christopher L. Morton, Linda C. Harris, Mary K. Danks, John D. Schuetz and Philip M. Potter
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 699-705; DOI: https://doi.org/10.1124/jpet.102.044149

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

p53-Mediated Regulation of Expression of a Rabbit Liver Carboxylesterase Confers Sensitivity to 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)

Monika Wierdl, Christopher L. Morton, Linda C. Harris, Mary K. Danks, John D. Schuetz and Philip M. Potter
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 699-705; DOI: https://doi.org/10.1124/jpet.102.044149
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