Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2'-deoxycytidine as a possible mechanism of chemotherapeutic action.
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 X DBA/2 F1 mice with L1210 leukemia were given a 15-hr i.v. infusion of 5-aza-dCyd at a total dose ranging from 0.5 mg/kg (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 found to be 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.
D044503:5-Methylcytosine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives / Q000032:analysis; D004247:DNA / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice
D000970:Antineoplastic Agents; D044503:5-Methylcytosine; D000077209:Decitabine; D003596:Cytosine; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine