This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, L. H. Articles by Reineke, L. M. Search for Related Content PubMed PubMed Citation Articles by Li, L. H. Articles by Reineke, L. M.

Cytotoxicity and Mode of Action of 5-Azacytidine on L1210 Leukemia¹

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

This study attempts to determine the primary actions of 5-azacytidine (5-azaCR) on L1210 leukemia. This agent was cytotoxic toward L1210 cells growing in culture with 50 and 90% inhibition dose values of 0.019 and circa 0.15 µg/ml, respectively. 5-AzaCR inhibits the incorporation of tritiated thymidine or deoxyadenosine into DNA to a greater extent than it inhibits the incorporation of tritiated uridine into RNA. Similar results were obtained with ascitic cells isolated from leukemic mice. Equimolar amounts of cytidine reduced the inhibition of DNA synthesis, as well as the inhibition of cell growth in culture caused by 5-azaCR. Uridine, but not deoxycytidine or deoxyuridine, was also effective, but to a lesser extent than was cytidine. With cell-free extracts isolated from L1210 cells in culture, no significant effect was found on enzyme systems directly or indirectly involved in DNA synthesis.

With 5-azaCR-4-¹⁴C as the precursor, this agent was found to be phosphorylated in all leukemic tissues studied. The majority of phosphorylated products existed as the triphosphate in ascitic and cultured L1210 cells. A portion (10 to 20%) of all these phosphorylated derivatives appeared to be further reduced to deoxyribonucleoside di- and/or triphosphate forms. 5-AzaCR was also incorporated into polynucleotides in all tissues studied and incorporated into both RNA (80 to 90% total incorporated radioactivity) and DNA fractions (10 to 20%) in L1210 cells in culture. In the presence of cytidine, phosphorylation of 5-azaCR, subsequent reduction, and incorporation into polynucleotides were greatly inhibited.

A probable mechanism of action of 5-azaCR on L1210 leukemia is proposed.

¹ This investigation was supported in part by Contract PH43-68-1023 with Chemotherapy, National Cancer Institute, NIH, Bethesda, Maryland. A preliminary report (18) was presented at the 60th Annual Meeting of the American Association for Cancer Research, March, 1969.

Received 3/30/70. Accepted 7/21/70.

This article has been cited by other articles:

				D. Lavelle, Y. Saunthararajah, and J. DeSimone DNA methylation and mechanism of action of 5-azacytidine Blood, February 15, 2008; 111(4): 2485 - 2485. [Full Text] [PDF]

				J. R Kuykendall 5-Azacytidine and Decitabine Monotherapies of Myelodysplastic Disorders Ann. Pharmacother., October 1, 2005; 39(10): 1700 - 1708. [Abstract] [Full Text] [PDF]

				W.-G. Zhu, T. Hileman, Y. Ke, P. Wang, S. Lu, W. Duan, Z. Dai, T. Tong, M. A. Villalona-Calero, C. Plass, et al. 5-Aza-2'-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation J. Biol. Chem., April 9, 2004; 279(15): 15161 - 15166. [Abstract] [Full Text] [PDF]

				J. Goffin and E. Eisenhauer DNA methyltransferase inhibitors--state of the art Ann. Onc., November 1, 2002; 13(11): 1699 - 1716. [Abstract] [Full Text] [PDF]

				L. R. Silverman, E. P. Demakos, B. L. Peterson, A. B. Kornblith, J. C. Holland, R. Odchimar-Reissig, R. M. Stone, D. Nelson, B. L. Powell, C. M. DeCastro, et al. Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B J. Clin. Oncol., May 15, 2002; 20(10): 2429 - 2440. [Abstract] [Full Text] [PDF]