5-Azacytidine potentiates initiation induced by carcinogens in rat liver

Abstract

To test the validity of the hypothesis that hypomethylation of DNA plays an important role in the initiation of carcinogenic process, 5-azacytidine (5-AzC) (10 mg/kg), an inhibitor of DNA methylation, was given to rats during the phase of repair synthesis induced by the three carcinogens, benzo[a]-pyrene (200 mg/kg), N-methyl-N-nitrosourea (60 mg/kg) and 1,2-dimethylhydrazine (1,2-DMH) (100 mg/kg). The initiated hepatocytes in the liver were assayed as the gamma-glutamyltransferase (gamma-GT) positive foci formed following a 2-week selection regimen consisting of dietary 0.02% 2-acetylaminofluorene coupled with a necrogenic dose of CCl4. The results obtained indicate that with all three carcinogens, administration of 5-AzC during repair synthesis increased the incidence of initiated hepatocytes, for example 10-20 foci/cm2 in 5-AzC and carcinogen-treated rats compared with 3-5 foci/cm2 in rats treated with carcinogen only. Administration of [3H]-5-azadeoxycytidine during the repair synthesis induced by 1,2-DMH further showed that 0.019 mol % of cytosine residues in DNA were substituted by the analogue, indicating that incorporation of 5-AzC occurs during repair synthesis. In the absence of the carcinogen, 5-AzC given after a two thirds partial hepatectomy, when its incorporation should be maximum, failed to induce any gamma-GT positive foci. The results suggest that hypomethylation of DNA per se may not be sufficient for initiation. Perhaps two events might be necessary for initiation, the first caused by the carcinogen and a second involving hypomethylation of DNA.

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes

“…2) corroborates pervious study in other cancers (19). Although the role of global hypomethylation is unclear, several animal experiments using DNA methylation inhibitors (39,40) are indicative of its involvement in oncogenesis and tumor progression. The hypermethylation of CpG islands observed in our study (Fig.…”

DNA methylation in cancer: too much, but also too little

“…The biological significance of DNA hypomethylation in cancer is less understood. Nonetheless, experiments involving DNA methylation inhibitors in vivo and in vitro (Carr et al, 1984;Denda et al, 1985;Thomas and Williams, 1992) or analysis of DNA methyltransferase-deficient mice (unpublished data, L Jackson-Grusby and R Jaenisch cited in Ehrlich, 2000) indicate the importance of induced DNA hypomethylation to oncogenesis. Studies of tumorigenesis in rodents fed methyl-deficient diets (reviewed in Poirier, 1994 andEhrlich, 2000) are in accord with a causative role for DNA hypomethylation in cancer, although the contribution of carcinogenic effects of these diets other than changes in DNA methylation is unclear (Pogribny et al, 1995).…”

Effect of Glycine on the Induction of Orotic Aciduria and Urinary Bladder Tumorigenesis in the Rat

“…This speculation is based on the rationale that glycine is utilized for the synthesis of guanidoacetic acid which can trap methyl groups to yield creatinine thereby creating a hypomethylated state. It is known that hypomethylation plays a role in the initiation step ofthe liver carcinogenic process (3,4).…”