INHIBITION OF DNA METHYLATION IN L1210-LEUKEMIC CELLS BY 5-AZA-2'-DEOXYCYTIDINE AS A POSSIBLE MECHANISM OF CHEMOTHERAPEUTIC ACTION

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (8) , 3493-3496
Abstract
The relationship between antineoplastic activity of 5-aza-2''-deoxycytidine (5-aza-dCyd) in mice with L1210 leukemia and inhibition of DNA methylation was investigated. BALB/c .times. DBA/2 F1 mice with L1210 leukemia were given a 15-h i.v. infusion of 5-aza-dCyd at a total ranging from 0.5 (weak antineoplastic effect) to 22 mg/kg (very potent antineoplastic effect). The DNA of L1210 leukemia cells was isolated from 5-aza-dcyd-treated mice and tested for its ability to accept methyl groups from S-adenosyl-L-methionine in a reaction catalyzed by DNA methyltransferase. The methyl-accepting ability of leukemia cell DNA was dependent on the dose of 5-aza-dCyd, suggesting that this therapy induced significant changes in the level of methylation of the DNA. At the start of the 5-aza-dCyd infusion, mice were given i.p. injections of [6-3H]uridine, and the DNA of the L1210 leukemia cells was isolated at the end of therapy. Analysis of the labeled pyrimidine bases showed that 5-aza-dCyd produced a dose-dependent reduction in the 5-methylcytosine content of the DNA. Thus, there appears to be a correlation between the antileukemic activity of 5-aza-dCyd and its ability to inhibit DNA methylation.