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

被引:50
作者
Herranz, M
Martín-Caballero, J
Fraga, MF
Ruiz-Cabello, J
Flores, JM
Desco, M
Marquez, V
Esteller, M
机构
[1] Spanish Natl Canc Ctr, Canc Epigenet Lab, Madrid 28029, Spain
[2] Spanish Natl Canc Ctr, Anim Facil Unit, Madrid 28029, Spain
[3] Univ Complutense Madrid, Sch Vet, Inst Estudios Biofuncionales, Madrid, Spain
[4] Univ Complutense Madrid, Sch Vet, Dept Pathol, Madrid, Spain
[5] Univ Hosp Gregorio Maranon, Dept Expt Surg, Med Image Lab, Madrid, Spain
[6] NCI, Med Chem Lab, NIH, Frederick, MD 21701 USA
关键词
D O I
10.1182/blood-2005-05-2033
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1174 / 1177
页数:4
相关论文
共 24 条
[1]   Inhibition of DNA methylation and reactivation of silenced genes by zebularine [J].
Cheng, JC ;
Matsen, CB ;
Gonzales, FA ;
Ye, W ;
Greer, S ;
Marquez, VE ;
Jones, PA ;
Selker, EU .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2003, 95 (05) :399-409
[2]   Continuous zebularine treatment effectively sustains demethylation in human bladder cancer cells [J].
Cheng, JC ;
Weisenberger, DJ ;
Gonzales, FA ;
Liang, GN ;
Xu, GL ;
Hu, YG ;
Marquez, VE ;
Jones, PA .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (03) :1270-1278
[3]   Preferential response of cancer cells to zebularine [J].
Cheng, JC ;
Yoo, CB ;
Weisenberger, DJ ;
Chuang, J ;
Wozniak, C ;
Liang, GN ;
Marquez, VE ;
Greer, S ;
Orntoft, TF ;
Thykjaer, T ;
Jones, PA .
CANCER CELL, 2004, 6 (02) :151-158
[4]   Epigenetics in human disease and prospects for epigenetic therapy [J].
Egger, G ;
Liang, GN ;
Aparicio, A ;
Jones, PA .
NATURE, 2004, 429 (6990) :457-463
[5]   DNA methylation and cancer therapy: new developments and expectations [J].
Esteller, M .
CURRENT OPINION IN ONCOLOGY, 2005, 17 (01) :55-60
[6]   CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future [J].
Esteller, M .
ONCOGENE, 2002, 21 (35) :5427-5440
[7]   Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer [J].
Fraga, MF ;
Ballestar, E ;
Villar-Garea, A ;
Boix-Chornet, M ;
Espada, J ;
Schotta, G ;
Bonaldi, T ;
Haydon, C ;
Ropero, S ;
Petrie, K ;
Iyer, NG ;
Pérez-Rosado, A ;
Calvo, E ;
Lopez, JA ;
Cano, A ;
Calasanz, MJ ;
Colomer, D ;
Piris, MA ;
Ahn, N ;
Imhof, A ;
Caldas, C ;
Jenuwein, T ;
Esteller, M .
NATURE GENETICS, 2005, 37 (04) :391-400
[8]   A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors [J].
Fraga, MF ;
Herranz, M ;
Espada, J ;
Ballestar, E ;
Paz, MF ;
Ropero, S ;
Erkek, E ;
Bozdogan, O ;
Peinado, H ;
Niveleau, A ;
Mao, JH ;
Balmain, A ;
Cano, A ;
Esteller, M .
CANCER RESEARCH, 2004, 64 (16) :5527-5534
[9]   The silence of the genes:: epigenetic disturbances in haematopoietic malignancies [J].
Hackanson, B ;
Guo, YL ;
Lübbert, M .
EXPERT OPINION ON THERAPEUTIC TARGETS, 2005, 9 (01) :45-61
[10]   Mechanisms of disease: Gene silencing in cancer in association with promoter hypermethylation [J].
Herman, JG ;
Baylin, SB .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (21) :2042-2054