Abstract
5-Aza-2′-deoxycytidine (5-AZA-CdR) is a potent antileukemic agent whose inhibitory effects are blocked by deoxycytidine (1-3). In order to be active, 5-AZA-CdR must first be phosphorylated by the enzyme deoxycytidine kinase (4). Leukemic cells deficient in the enzyme are resistant to 5-AZA-CdR (5). The lethal action of 5-AZA-CdR is related to its incorporation into DNA (6,7). The incorporation of 5-azacytosine analogs into DNA has been shown to induce the expression of differentiated phenotypes (8). This induction of differentiation by 5-AZA-CdR appears to be related to the inhibition of DNA methylation produced by these analogs (8, 9).
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References
F, Sorm and J. Vesely, Effect of 5-AZA-2′-deoxycytidine against leukemic and hemopoietic tissues in AKR mice, Neoplasma (Bratisl.) 15: 339 (1968).
R.L. Momparler and F.A. Gonzales, Effect of intravenous infusion of 5-AZA-2′-deoxycytidine on survival time of mice with LI210 leukemia. Cancer Res., 38: 2673 (1978).
R.L. Momparler and J. Goodman, In vitro cytotoxic and biochemical effects of 5-AZA-2′-deoxycytidine. Cancer Res., 37: 1636 (1977).
R.L. Momparler and D. Derse, Kinetics of phosphorylation of 5-AZA-2′-deoxycytidine by deoxycytine kinase. Biochem. Pharmacol., 28: 1448 (1979).
J. Vesely, A. Cihak and F. Sorm, Characteristics of mouse leukemic cells resistant to 5-azacytidine and 5-AZA-2′-deoxycytidine. Cancer Res., 28: 1995 (1968).
J. Vesely and A. Cihak, Incorporation of a potent antileukemic agent, 5-AZA-2′-deoxycytidine, into DNA of cells from leukemic mice. Cancer Res., 37: 3684 (1977).
R.L. Momparler, J. Vesely, L.F. Momparler and G.E. Rivard, Synergistic action of 5-AZA-2′ deoxycytidine and 3-deazauridine on L1210 leukemic cells and EMT6 tumor cells. Cancer Res., 39: 3822 (1979).
P.A. Jones, S.M. Taylor, Cellular differentiation, cytidine analogs, and DNA methylation. Cell, 20: 85 (1980).
J. Bouchard and R.L. Momparler, Incorporation of 5-AZA-2′-deoxycyti-dine-5′triphosphate into DNA interactions with mammalian DNA polymerase and DNA methylase. Mol. Pharmacol., 24: 209 (1983).
A. Razin and A.D. Riggs, DNA methylation and gene function. Science, 210: 604 (1980).
J.D. McGhee and G.D. Grinder, Specific DNA methylation sites in the vicinity of the chicken β-globin genes. Nature, 280: 419 (1979).
M. Busslinger, J. Hurst and R.A. Flavell, DNA methylation and the regulation of globin gene expression. Cell, 34: 197 (1983).
L. Sachs, The differentiation of meloid leukemic cells. New possibilities for therapy. Br. J. Haematol., 40: 509 (1978).
R.L. Momparler, M.Y. Chu and G.A. Fischer, Studies on a new mechanism of resistance of L5178Y murine leukemic cells to cytosine arabinoside Biochim. Biophys. Acta, 161: 481 (1968).
S. Grant, F. Rauscher, J. Margolin and E. Cadman, Dose and schedule depedent activation and drug synergism between thymidine and 5-AZA-2ȃ-deoxycytidine in a human promyelocytc leukemia cell line. Cancer Res., 42: 519 (1982).
G. Bjursell and P. Reichard, Effect of thymidine in deoxyribonucleoside triphosphate pools and deoxyribonucleic acid systhesis in Chinese hamster ovary cells. J. Biol. Chem., 218: 3904 (1973).
E.C. Moore and R.B. Hurlbert, Regulation of Mammalian deoxyribonucleo-tide biosynthesis by nucleotides as activators and inhibitors. J. Biol. Chem., 241: 4802 (1966).
F. Scarano, G. Geraci and M. Rossi, Deoxycytidylate aminohydrolase. II. Kinetic properties. The activatory effect of deoxycytidine triphosphate and the inhibitory effect of deoxythymidine triphosphate. Biochemistry, 6: 192–201 (1967).
B.R. de Saint-Vincent and M. De champs, and G. Buttin, The modulation of the thymidine triphosphate pool of Chinese hamster cells by dCMP deaminase and UDP reductase: thymidine auxotrophy induced by CTP in dCMP deaminase-deficient line. J. Biol. Chem., 255: 162 (1980).
G. Weinberg, B. Ullman and D.W. Martin, Mutator phenotypes in mammalian cell mutants with distinct biochemical defects and abnormal deoxyribonucleoside triphosphate pools. Proc. Natl. Acad. Sci. (USA), 78: 2447 (1981).
W.R. Mancini and Y.C. Cheng, Human deoxycytidylate deaminase substrate and regulator specificities and their chemotherapeutic implications. Mo. Pharmacol., 23: 159–164 (1983).
R.L. Momparler, M. Rossi, J. Bouchard, C. Vaccaro, L.F. Momparler and S. Bartolucci, Kinetic Interaction of 5-AZA-2′-deoxycytidine-5′-monophosphate and Its 5′-triphosphate with deoxycytodilate deamirase. Mol. Pharmacol., 25: 436 (1984).
R.L. Momparler, L.F. Momparler and J. Samson, Comparison of the antileu-kemic activity of 5-AZA-2′-deoxycytidine, 1-β-D-arabinofuranosyl-cytosine and 5-azacytidine against L1210 leukemie. Leukemie Res., 8: 1043 (1984).
J. Bouchard, Pharmacologie moléculaire de la 5-AZA-2′-deoxycytidine. Ph.D Thesis., Univ. Montréal (1983).
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Momparler, R.L. et al. (1986). 5-AZA-2′-Deoxycytidine Synergistic action with Thymidine on Leukemic Cells and Interaction of 5-AZA-dCMP with dCMP Deaminase. In: Nyhan, W.L., Thompson, L.F., Watts, R.W.E. (eds) Purine and Pyrimidine Metabolism in Man V. Advances in Experimental Medicine and Biology, vol 195B. Springer, New York, NY. https://doi.org/10.1007/978-1-4684-1248-2_24
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DOI: https://doi.org/10.1007/978-1-4684-1248-2_24
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