Chemical decomposition of 5-aza-2′-deoxycytidine (Decitabine): Kinetic analyses and identification of products by NMR, HPLC, and mass spectrometry

Chemical Research in Toxicology

Volumn 22, Issue 6, 2009, Pages 1194-1204

  Rogstad, Daniel K ^a   Herring, Jason L ^a   Theruvathu, Jacob A ^a   Burdzy, Artur ^a   Perry, Christopher C ^a   Neidigh, Jonathan W ^a   Sowers, Lawrence C ^a  

^a LOMA LINDA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; STABLE ISOTOPE; TRIAZINE;

ARTICLE; CHEMICAL STRUCTURE; CONFORMATION; DRUG DECOMPOSITION; GAS CHROMATOGRAPHY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HYDROLYSIS; ISOTOPE DILUTION ASSAY; MASS SPECTROMETRY; MATHEMATICAL MODEL; PROTON NUCLEAR MAGNETIC RESONANCE; RING OPENING; TIME OF FLIGHT MASS SPECTROMETRY; ULTRAVIOLET SPECTROPHOTOMETRY;

AZACITIDINE; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DNA MODIFICATION METHYLASES; ENZYME INHIBITORS; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; HALF-LIFE; HYDROGEN-ION CONCENTRATION; KINETICS; MAGNETIC RESONANCE SPECTROSCOPY; SPECTROPHOTOMETRY, ULTRAVIOLET; TEMPERATURE; TIME FACTORS;

EID: 67449100820     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx900131u     Document Type: Article

References (39)

1. Momparler, R. L., and Derse, D. (1979) Kinetics of phosphorylation of 5-aza-2′-deoxycytidine by deoxycytidine kinase. Biochem. Pharmacol. 28, 1443-1444. (Pubitemid 9174327)
2. Bouchard, J., and Momparler, R. L. (1983) Incorporation of 5-aza-2′-deoxycytidine-5′-triphosphate into DNA. Interactions with mammalian DNA polymerase α and DNA methylase. Mol. Pharmacol. 24, 109-114.
3. Santi, D. V., Norment, A., and Garrett, C. E. (1984) Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc. Natl. Acad. Sci. U.S.A. 81, 6993-6997. (Pubitemid 15216684)
4. Christman, J. K. (2002) 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21, 5483-5495. (Pubitemid 34983483)
5. Bender, C. M., Pao, M. M., and Jones, P. A. (1998) Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res. 58, 95-101. (Pubitemid 28027723)
6. Daskalakis, M., Nguyen, T. T., Nguyen, C., Guldberg, P., Kohler, G., Wijermans, P., Jones, P. A., and Lubbert, M. (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment. Blood 100, 2957-2964.
7. Kantarjian, H., Issa, J.-P. J., Rosenfeld, C. S., Bennett, J. M., Albitar, M., DiPersio, J., Klimek, V., Slack, J., de Castro, C., Ravandi, F., Helmer, R, Shen, L., Nimer, S. D., Leavitt, R., Raza, A., and Saba, H. (2006) Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer 106, 1794-1803.
8. Kantarjian, H. M., O'Brien, S., Cortes, J., Giles, F. J., Faderl, S., Issa, J.-P., Garcia-Manero, G., Rios, M. B., Shan, J., Andreeff, M., Keating, M., and Talpaz, M. (2003) Results of decitabine (5-aza-2′-deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 98, 522-528. (Pubitemid 36885992)
9. Schrump, D. S., Fischette, M. R., Nguyen, D. M., Zhao, M., Xinmin, L., Kunst, T. F., Hancox, A., Hong, J. A., Chen, G. A., Pishchik, V., Figg, W. D., Murgo, A. J., and Steinberg, S. M. (2006) Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin. Cancer Res. 12, 5777-5785. (Pubitemid 44629609)
10. Appleton, K., Mackay, H. J., Judson, I., Plumb, J. A., McCormick, C., Strathdee, G., Lee, C., Barrett, S., Reade, S., Jadayel, D., Tang, A., Bellenger, K., Mackay, L., Setanoians, A., Schatzlein, A., Twelves, C., Kaye, S. B., and Brown, R. (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J. Clin. Oncol. 25, 4603-4609. (Pubitemid 350035319)
11. DeSimone, J., Koshy, M., Dorn, L., Lavelle, D., Bressler, L., Molokie, R., and Talischy, N. (2002) Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99, 3905-3908. (Pubitemid 35332025)
12. Juttermann, R., Li, E., and Jaenisch, R. (1994) Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl. Acad. Sci. U.S.A. 91, 11797-11801. (Pubitemid 24985095)
13. Jackson-Grusby, L., Laird, P. W., Magge, S. N., Moeller, B. J., and Jaenisch, R. (1997) Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc. Natl. Acad. Sci. U.S.A. 94, 4681-4685. (Pubitemid 27194303)
14. Palii, S. S., Van Emburgh, B. O., Sankpal, U. T., Brown, K. D., and Robertson, K. D. (2008) DNA methylation inhibitor 5-aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol. Cell. Biol. 28, 752-771.
15. Karpf, A. R., Moore, B. C., Ririe, T. O., and Jones, D. A. (2001) Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2′-deoxycytidine. Mol. Pharmacol. 59, 751-757. (Pubitemid 32274003)
16. Ghoshal, K., Datta, J., Majumder, S., Bai, S., Kutay, H., Motiwala, T., and Jacob, S. T. (2005) 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell. Biol. 25, 4727-4741. (Pubitemid 40705775)
17. Lin, K.-T., Momparler, R. L., and Rivard, G. E. (1981) Highperformance liquid chromatographic analysis of chemical stability of 5-aza-2′- deoxycytidine. J. Pharm. Sci. 70, 1228-1232. (Pubitemid 12166545)
18. Liu, Z., Marcucci, G., Byrd, J. C., Grever, M., Xiao, J., and Chan, K. K. (2006) Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5-aza- 2′-deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method. Rapid Commun. Mass Spectrom. 20, 1117-1126.
19. Yoo, C. B., Jeong, S., Egger, G., Liang, G., Phiasivongsa, P., Tang, C., Redkar, S., and Jones, P. A. (2007) Delivery of 5-aza-2′- deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 67, 6400-6408. (Pubitemid 47037524)
20. Stresemann, C., and Lyko, F. (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer 123, 8-13. (Pubitemid 351705186)
21. Hajek, M., Votruba, I., Holy, A., Krecmerova, M., and Tloustova, E. (2008) Alpha anomer of 5-aza-2′-deoxycytidine down-regulates hTERT mRNA expression in human leukemia HL-60 cells. Biochem. Pharmacol. 75, 965-972. (Pubitemid 351181426)
22. Chan, K. K., Giannini, D. D., Staroscik, J. A., and Sadee, W. (1979) 5-Azacytidine hydrolysis kinetics measured by high-pressure liquid chromatography and 13C-NMR spectroscopy. J. Pharm. Sci. 68, 807-812. (Pubitemid 9224244)
23. Vesely, J., and Piskala, A. (1984) Effects of the R-D-anomer of 5-aza-2′-deoxycytidine on L1210 mouse leukemic cells in vitro and in vivo. Cancer Res. 44, 5165-5168. (Pubitemid 15204483)
24. Liu, M.-C., Luo, M.-Z., Mozdziesz, D. E., Lin, T.-S., Dutschman, G. E., Cheng, Y.-C., and Sartorelli, A. C. (1999) Synthesis of 2′-methylene- substituted 5-azapyrimidine, 6-azapyrimidine, and 3-deazaguanine nucleoside analogues as potential antitumor/antiviral agents. Nucleosides Nucleotides 18, 55-72. (Pubitemid 29093201)
25. Ben-Hattar, J., and Jiricny, J. (1986) An improved synthesis of 2′-deoxy-5-azacytidine by condensation of a 9- fluorenylmethoxycarbonylprotected sugar onto the silylated base. J. Org. Chem. 51, 3211-3213. (Pubitemid 16002870)
26. Hartenstein, R., and Fridovich, I. (1967) Amidinourea formate, a precursor of 2-amino-4-hydroxy-s-triazine. J. Org. Chem. 32, 1653-1654.
27. Beisler, J. A. (1978) Isolation, characterization, and properties of a labile hydrolysis product of the antitumor nucleoside, 5-azacytidine. J. Med. Chem. 21, 204-208. (Pubitemid 8269368)
28. Braun, S., Kalinowski, H.-O., and Berger, S. (1998) 150 and More Basic NMR Experiments, pp140-143, Wiley-VCH, Weinheim, Germany.
29. Liu, M., Mao, X., Ye, C., Huang, H., Nicholson, J. K., and Lindon, J. C. (1998) Improved WATERGATE pulse sequences for solvent suppression in NMR spectroscopy. J. Magn. Reson. 132, 125-129. (Pubitemid 128450594)
30. Rodiguin, N. M., and Rodiguina, E. N. (1964) Consecutive Chemical Reactions, pp. 29-31, D. Van Nostrand, Princeton, NJ.
31. Motulsky, H., and Christopoulos, A. (2005) Fitting Models to Biological Data Using Linear and Nonlinear Regression, pp 109-117, GraphPad Software, Inc., San Diego, CA.
32. Tomankova, H., and Zyka, J. (1980) Study of the time dependence of the stability of 5-aza-2′-deoxycytidine in acid medium. Microchem. J. 25, 281-288.
33. Notari, R. E., and DeYoung, J. L. (1975) Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions. J. Pharm. Sci. 64, 1148-1157.
34. Dubey, I., Pratviel, G., Robert, A., and Meunier, B. (2001) Convenient method for the preparation of 2′-deoxyribosylurea by thymidine oxidation and NMR study of both anomers. Nucleosides Nucleotides Nucleic Acids 20, 1463-1471. (Pubitemid 32808137)
35. Wallace, S. S. (2002) Biological consequences of free radical-damaged DNA bases. Free Radical Biol. Med. 33, 1-14. (Pubitemid 34681001)
36. Chabot, G. G., Bouchard, J., and Momparler, R. L. (1983) Kinetics of deamination of 5-aza-2′-deoxycytidine and cytosine arabinoside by human liver cytidine deaminase and its inhibition by 3-deazauridine, thymidine or uracil arabinoside. Biochem. Pharmacol. 32, 1327-1328. (Pubitemid 13135651)
37. Fojtova, M., Piskala, A., Votruba, I., Otmar, M., Bartova, E., and Kovarik, A. (2007) Efficacy of DNA hypomethylating capacities of 5-aza-2′-deoxycytidine and its alpha anomer. Pharmacol. Res. 55, 16-22. (Pubitemid 46108582)
38. Peery, A., and LePage, G. A. (1969) Nucleotide formation from Rand β-2′-deoxythioguanosine in extracts of murine and human tissues. Cancer Res. 29, 617-623.
39. Zielinski, W. S., and Sprinzl, M. (1984) Chemical synthesis of 5-azacytidine nucleotides and preparation of tRNAs containing 5-azacytidine in its 3′-terminus. Nucleic Acids Res. 12, 5025-5036.