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Tumor Biology

Inactivation of p53 Enhances Sensitivity to Multiple Chemotherapeutic Agents

Douglas S. Hawkins, G. William Demers and Denise A. Galloway
Douglas S. Hawkins
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G. William Demers
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Denise A. Galloway
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DOI:  Published February 1996
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Abstract

Many tumor types have p53 and/or RB mutations, and it is unclear what role the mutations of these tumor suppressor genes have on the efficacy of chemotherapeutic agents. The effect of p53 and RB inactivation on sensitivity to chemotherapeutic drugs was examined using a model system in which p53 or RB was inactivated in normal human foreskin fibroblasts (HFFs) by acute expression of human papillomavirus (HPV) 16E6 or 16E7. Cytotoxicity assays showed that HFFs expressing HPV 16E6 were 6- to 9-fold more sensitive to the DNA crosslinkers cisplatin and carboplatin and 7.8- to 11.5-fold more sensitive to the tubulin polymerizing agent paclitaxel than were LXSN-expressin cells. Analysis of mouse embryonal fibroblasts lacking p53 (p53-/-) compared with mouse embryonal fibroblasts homozygous (p53+/+) and heterozygous (p53+/-) for wild-type p53 confirmed the role of p53 in the enhanced sensitivity to cisplatin. Treatment with the alkylating agents melphalan and nitrogen mustard resulted in 3.8- to 7.3-fold greater sensitivity in HPV 16E6- or 16E7-expressing cells compared with LXSN-expressing cells. Enhanced sensitivity to cisplatin in cells lacking p53 function was explored by examination of its effects on cell cycle progression after exposure. When treated with cisplatin, HFFs expressing 16E6 showed delayed progression through S phase relative to HFFs expressing LXSN. The delay in S phase progression was coincident with the induction of p53 protein levels in LXSN-containing HFFs, suggesting a role for p53 in DNA repair of cisplatin-induced damage. These results indicate that the inactivation of p53 in the absence of other genetic alterations leads to enhanced sensitivity to multiple chemotherapeutic agents rather than to increased resistance.

Footnotes

  • ↵1 This work was supported in part by National Cancer Institute grant CA64795 (to D. A. G.) and National Cancer Institute Pediatric Oncology Training Grant CA09351 (to D. S. H.).

  • ↵2 To whom requests for reprints should be addressed, at Cancer Biology Program, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, CI-015, Seattle, WA 98104. Phone: (206) 667-4506; Fax: (206) 667-5815.

  • Received August 15, 1995.
  • Accepted December 5, 1995.
  • ©1996 American Association for Cancer Research.
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February 1996
Volume 56, Issue 4
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Inactivation of p53 Enhances Sensitivity to Multiple Chemotherapeutic Agents
Douglas S. Hawkins, G. William Demers and Denise A. Galloway
Cancer Res February 15 1996 (56) (4) 892-898;

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Inactivation of p53 Enhances Sensitivity to Multiple Chemotherapeutic Agents
Douglas S. Hawkins, G. William Demers and Denise A. Galloway
Cancer Res February 15 1996 (56) (4) 892-898;
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