Abstract
Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and in human tumors. This has led to the pursuit of DNA methyltransferase inhibition as a drug target. 5-Aza-2′-deoxycytidine [5-aza-CdR (decitabine)], a potent inhibitor of DNA methyltransferase, is a drug currently in clinical trials for the treatment of solid tumors and leukemia. The efficacy of 5-aza-CdR may be related to the induction of methylation-silenced tumor suppressor genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test the hypothesis that 5-aza-CdR treatment is perceived as DNA damage, as assessed by the activation of the tumor suppressor p53. We show that 1) colon tumor cell lines expressing wild-type p53 are more sensitive to 5-aza-CdR mediated growth arrest and cytotoxicity; 2) the response to 5-aza-CdR treatment includes the induction and activation of wild-type but not mutant p53 protein; and 3) the induction of the downstream p53 target gene p21 is partially p53-dependent. The induction of p53 protein after 5-aza-CdR treatment did not correlate with an increase in p53 transcripts, indicating that hypomethylation at the p53 promoter does not account for the p53 response. It is relevant that 5-aza-CdR has shown the greatest promise in clinical trials for the treatment of chronic myelogenous leukemia, a malignancy in which functional p53 is often retained. Our data raise the hypothesis that p53 activation may contribute to the clinical efficacy and/or toxicity of 5-aza-CdR.
Footnotes
- Received November 2, 2000.
- Accepted January 3, 2001.
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Send reprint requests to: Dr. David A. Jones, Division of Molecular Pharmacology, Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112. E-mail:david.jones{at}hci.utah.edu
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This work was supported by a Postdoctoral Fellowship PF-99–151-01-CDD from the American Cancer Society (to A.R.K.) and by National Institutes of Health P01-CA73992 (to D.A.J.).
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This work was previously presented under the title “Impact of p53 status on the response of tumor cells to 5-aza-2′-deoxycytide treatment” at the American Association of Cancer Research Annual Meeting, San Francisco, CA, 1–5 April, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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