The Novel DNA Methylation Inhibitor Zebularine Is Effective Against the Development of Murine T-cell Lymphoma

Blood. 2006 Feb 1;107(3):1174-7. doi: 10.1182/blood-2005-05-2033. Epub 2005 Oct 20.

Abstract

Gene silencing by CpG island promoter hypermethylation has awakened the interest for DNA demethylating agents as chemotherapy drugs. Zebularine (1-[beta-D-ribofuranosil]-1,2-dihydropyrimidin-2-1) has been recently described as a new DNA methylation inhibitor. Here we have studied its effects in a mouse model of radiation-induced lymphomagenesis using nuclear magnetic resonance (NMR) and positron emission tomography (PET). All control animals presented large thymic T lymphomas and died between 4 and 5.5 months. In contrast, 40% (12 of 30) of zebularine-treated animals were still alive after 1 year (Kaplan-Meier P < .001). NMR and PET imaging showed that surviving animals presented a thymus structure/volume similar to normal mice of the same age. Most important, zebularine demonstrated a complete lack of toxicity in nonirradiated control mice. DNA hypomethylation induced by zebularine occurred in association with depletion in extractable DNA methyltransferase 1 protein. Thus, our data support the role of zebularine as a DNA demethylating agent with antitumor activity and little toxicity.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Cell Transformation, Neoplastic / drug effects
  • Cytidine / administration & dosage
  • Cytidine / adverse effects
  • Cytidine / analogs & derivatives*
  • DNA Methylation / drug effects*
  • Drug Evaluation, Preclinical
  • Gene Silencing / drug effects*
  • Injections, Intraperitoneal
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell / pathology
  • Mice
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology

Substances

  • Antineoplastic Agents
  • Cytidine
  • pyrimidin-2-one beta-ribofuranoside