Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells

Bin Yang, James Eshleman, Nathan A. Berger, Sanford D. Markowitz

Research output: Contribution to journalArticle

Abstract

Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a cell cycle pause or to potentiate cell death via apoptosis. Wild-type p53 in different cell types has similarly been associated with either enhancement of or increased resistance to the cytotoxicity of many cancer therapeutic agents. We have constructed a colorectal cancer cell line bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor. Induction of wild-type p53 by isopropyl-β-thiogalactopyranoside in these cells induces a reversible growth arrest but does not induce cell death. However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5-fluorouracil, two agents that are used clinically in the treatment of colorectal cancer. We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer. These findings suggest that the common loss of wild-type p53 in many colorectal cancers may play a role in the clinical resistance of these tumors to anticancer agents. Although some cancer cells may not be directly killed by p53 gene therapy, our findings suggest that genetic alteration of some cancers to induce wild-type p53 may increase their sensitivity to cytotoxic gene therapy.

Original languageEnglish (US)
Pages (from-to)1649-1657
Number of pages9
JournalClinical Cancer Research
Volume2
Issue number10
StatePublished - Oct 1996
Externally publishedYes

Fingerprint

Colonic Neoplasms
Colorectal Neoplasms
Genetic Therapy
Neoplasms
Proteins
Cell Death
Alleles
Lac Repressors
Thiogalactosides
Topotecan
Camptothecin
p53 Genes
Therapeutics
Fluorouracil
DNA Repair
Antineoplastic Agents
DNA Damage
Cell Cycle
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells. / Yang, Bin; Eshleman, James; Berger, Nathan A.; Markowitz, Sanford D.

In: Clinical Cancer Research, Vol. 2, No. 10, 10.1996, p. 1649-1657.

Research output: Contribution to journalArticle

Yang, Bin ; Eshleman, James ; Berger, Nathan A. ; Markowitz, Sanford D. / Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells. In: Clinical Cancer Research. 1996 ; Vol. 2, No. 10. pp. 1649-1657.
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