The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma.

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.

• Authors: Michel Herranz, Juan Martín-Caballero, Mario F Fraga, Jesús Ruiz-Cabello, Juana Maria Flores, Manuel Desco, Victor Marquez, Manel Esteller
• Journal: Blood (Blood) Vol. 107 Issue 3 Pg. 1174-7 (Feb 01 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16239434 (Publication Type: Journal Article)

Chemical References

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

Topics

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