Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors.
OBJECTIVE
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.


CONCLUSIONS
Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.
Chan
Anthony T C
AT
Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China.
Tao
Qian
Q
Robertson
Keith D
KD
Flinn
Ian W
IW
Mann
Risa B
RB
Klencke
Barbara
B
Kwan
Wing Hong
WH
Leung
Thomas Wai-Tong
TW
Johnson
Philip J
PJ
Ambinder
Richard F
RF
D000957:Antigens, Viral, Tumor / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology*; D001483:Base Sequence; D019175:DNA Methylation; D004279:DNA, Viral / Q000378:metabolism; D015257:DNA-Cytosine Methylases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000821:virology; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000821:virology; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic
D000957:Antigens, Viral, Tumor; D004279:DNA, Viral; D004791:Enzyme Inhibitors; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases; D001374:Azacitidine