RESUMEN
Cyclooxygenase-2 (COX-2) has been associated with cell growth regulation, tissue remodeling, and carcinogenesis. Ectopic expression of COX-2 in hepatocytes constitutes a nonphysiological condition ideal for evaluating the role of prostaglandins (PGs) in liver pathogenesis. The effect of COX-2-dependent PGs in chronic liver disease, hepatitis, fibrosis, and chemical hepatocarcinogenesis, has been investigated in transgenic (Tg) mice that express human COX-2 in hepatocytes and in Tg hepatic human cell lines. We have used three different complementary approaches: i) diethylnitrosamine (DEN)-induced chemical hepatocarcinogenesis in COX-2 Tg mice, ii) DEN/phenobarbital treatment of human COX-2 Tg hepatocyte-like cells, and iii) COX-2 Tg hepatocyte-like cells implants in nude mice. The data suggest that PGs produced by COX-2 in hepatocytes promoted mild hepatitis in 60-week-old mice, as assessed by histological examination, but failed to contribute to the development of liver fibrogenesis after methionine- and choline-deficient diet treatment. Moreover, liver injury, collagen content, and hepatic stellate cell activation were equally severe in wild-type and COX-2 Tg mice. The contribution of COX-2-dependent PGs to the development of DEN-induced hepatocarcinogenesis was evaluated in Tg mice, Tg hepatocyte-like cells, and nude mice and the analysis revealed that COX-2 expression favors the development of preneoplastic foci without affecting malignant transformation. Endogenous COX-2 expression in wild-type mice is a late event in the development of hepatocellular carcinoma.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Hepatocitos/enzimología , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/patología , Envejecimiento/patología , Animales , Peso Corporal , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Ciclina E/metabolismo , Dietilnitrosamina , Regulación Neoplásica de la Expresión Génica , Hepatitis/complicaciones , Hepatitis/patología , Hepatocitos/patología , Humanos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/enzimología , Cirrosis Hepática/patología , Neoplasias Hepáticas/genética , Ratones , Ratones Desnudos , Ratones Transgénicos , Tamaño de los Órganos , Lesiones Precancerosas/inducido químicamente , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transgenes/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.