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Inhibition of DNA Methylation in L1210 Leukemic Cells by 5-Aza-2'-deoxycytidine as a Possible Mechanism of Chemotherapeutic Action¹

Department of Biochemistry, School of Medicine, University of Southern California, Los Angeles [P. A. J.], and Division of Hematology-Oncology, Childrens Hospital of Los Angeles, Los Angeles, California 90027 [V. L. W., P. A. J.], and Département de Pharmacologie, Université de Montréal, and Centre de Recherche Pédiatrique, Hôpital Sainte-Justine, Montreal, Quebec, Canada H3T 1C5 [R. L. M.]

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.

¹ This investigation was supported by USPHS Grants GM 25739, Grant MA6356 from the Medical Research Council of Canada, and by LEUCAN.

² To whom requests for reprints should be addressed, at Centre de Recherche Pédiatrique, Hpital Sainte-Justine, 3175 Chemin Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5.

Received 8/16/82. Accepted 4/19/83.

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