The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma.
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.
Herranz
Michel
M
Cancer Epigenetics Laboratory and the Animal Facility Unit, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Martín-Caballero
Juan
J
Fraga
Mario F
MF
Ruiz-Cabello
Jesús
J
Flores
Juana Maria
JM
Desco
Manuel
M
Marquez
Victor
V
Esteller
Manel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003562:Cytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019175:DNA Methylation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D020868:Gene Silencing / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside