Originally published as JCO Early Release 10.1200/JCO.2004.04.185 on March 8 2004

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, A. T.C. Articles by Ambinder, R. F. Search for Related Content PubMed PubMed Citation Articles by Chan, A. T.C. Articles by Ambinder, R. F. Related Articles Related Editorial

Azacitidine Induces Demethylation of the Epstein-Barr Virus Genome in Tumors

From the Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China; Cancer Epigenetics/Tumor Virology Laboratory, Johns Hopkins Singapore, Singapore; Epigenetic Gene Regulation and Cancer Section, National Cancer Institute, National Institutes of Health, Bethesda; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Medicine, University of California San Francisco-Mt. Zion Hospital, San Francisco, CA

Address reprint requests to Richard F. Ambinder, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Bldg Rm 389, 1650 Orleans St, Baltimore, MD 21231; e-mail: ambinri{at}jhmi.edu

PURPOSE: To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients.

METHODS: Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression.

RESULTS: Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance.

CONCLUSION: Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.

Research funded by National Institutes of Health grants PO1 CA15396 "EBV-related tumors" and UOI CA70062 "AIDS-associated malignancies clinical trials in a cooperative group."

Anthony T.C. Chan and Qian Tao contributed equally to the work.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

Related Editorial

• Cancer Chemotherapy Targeted at Reactivating the Expression of Epigenetically Inactivated Genes
  Jonathan E. Dowell and John D. Minna
  JCO 2004 22: 1353-1355 [Full Text]

This article has been cited by other articles:

				D.-X. Fu, Y. C. Tanhehco, J. Chen, C. A. Foss, J. J. Fox, V. Lemas, J.-M. Chong, R. F. Ambinder, and M. G. Pomper Virus-Associated Tumor Imaging by Induction of Viral Gene Expression Clin. Cancer Res., March 1, 2007; 13(5): 1453 - 1458. [Abstract] [Full Text] [PDF]

				G. Francia, S. K. Green, G. Bocci, S. Man, U. Emmenegger, J. M.L. Ebos, A. Weinerman, Y. Shaked, and R. S. Kerbel Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents Mol. Cancer Ther., October 1, 2005; 4(10): 1484 - 1494. [Abstract] [Full Text] [PDF]

				C. Mund, B. Hackanson, C. Stresemann, M. Lubbert, and F. Lyko Characterization of DNA Demethylation Effects Induced by 5-Aza-2'-Deoxycytidine in Patients with Myelodysplastic Syndrome Cancer Res., August 15, 2005; 65(16): 7086 - 7090. [Abstract] [Full Text] [PDF]

				P. M. Bhende, W. T. Seaman, H.-J. Delecluse, and S. C. Kenney BZLF1 Activation of the Methylated Form of the BRLF1 Immediate-Early Promoter Is Regulated by BZLF1 Residue 186 J. Virol., June 15, 2005; 79(12): 7338 - 7348. [Abstract] [Full Text] [PDF]

				W. E. Samlowski, S. A. Leachman, M. Wade, P. Cassidy, P. Porter-Gill, L. Busby, R. Wheeler, K. Boucher, F. Fitzpatrick, D. A. Jones, et al. Evaluation of a 7-Day Continuous Intravenous Infusion of Decitabine: Inhibition of Promoter-Specific and Global Genomic DNA Methylation J. Clin. Oncol., June 10, 2005; 23(17): 3897 - 3905. [Abstract] [Full Text] [PDF]

				H. E. Heslop Biology and Treatment of Epstein-Barr Virus-Associated Non-Hodgkin Lymphomas Hematology, January 1, 2005; 2005(1): 260 - 266. [Abstract] [Full Text] [PDF]

				J. E. Dowell and J. D. Minna Cancer Chemotherapy Targeted at Reactivating the Expression of Epigenetically Inactivated Genes J. Clin. Oncol., April 15, 2004; 22(8): 1353 - 1355. [Full Text] [PDF]