Table of Contents
Chemotherapy Research and Practice
Volume 2011, Article ID 965826, 9 pages
http://dx.doi.org/10.1155/2011/965826
Research Article

Development of an Oral Form of Azacytidine: 𝟐 𝟑 𝟓 Triacetyl-5-Azacytidine

1Nevada Cancer Institute, One Breakthough Way, Las Vegas, NV 89135, USA
2St. Jude Children's Research Hospital, Memphis, TN 38105, USA
3The Hong Kong Polytechnic University, Kowloon, Hong Kong

Received 12 July 2011; Revised 14 September 2011; Accepted 21 September 2011

Academic Editor: G. J. Peters

Copyright © 2011 Amy Ziemba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Aul, N. Gattermann, and W. Schneider, “Age-related incidence and other epidemiological aspects of myelodysplastic syndromes,” British Journal of Haematology, vol. 82, no. 2, pp. 358–367, 1992. View at Google Scholar · View at Scopus
  2. P. Greenberg, “Myelodysplastic syndrome,” in Hematology: Basic Principles and Practice, R. Hoffman, E. Benz, and S. Shattil, Eds., pp. 2593–2615, Chruchill Livingston, New York, NY, USA, 2000. View at Google Scholar
  3. L. Silverman, “The myelodysplastic syndrome,” in Cancer Medicine, J. Holland, E. Frei, R. Bast, D. Kufe, D. Morton, and R. Weichselbaum, Eds., pp. 2593–2615, Williams and Wilkins, Baltimore, Md, USA, 1996. View at Google Scholar
  4. K. Foucar, R. M. Langdon II, and J. O. Armitage, “Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases,” Cancer, vol. 56, no. 3, pp. 553–561, 1985. View at Google Scholar · View at Scopus
  5. J. Kerkhofs, J. Hermans, H. L. Haak, and C. H. W. Leeksma, “Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases,” British Journal of Haematology, vol. 65, no. 1, pp. 73–81, 1987. View at Google Scholar · View at Scopus
  6. M. Benesch and H. J. Deeg, “Hematopoietic cell transplantation for adult patients with myelodysplastic syndromes and myeloproliferative disorders,” Mayo Clinic Proceedings, vol. 78, no. 8, pp. 981–990, 2003. View at Google Scholar · View at Scopus
  7. L. R. Silverman, E. P. Demakos, B. L. Peterson et al., “Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B,” Journal of Clinical Oncology, vol. 20, no. 10, pp. 2429–2440, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Kantarjlan, J. P. J. Issa, C. S. Rosenfeld et al., “Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study,” Cancer, vol. 106, no. 8, pp. 1794–1803, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. T. E. Fandy, “Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases,” Current Medicinal Chemistry, vol. 16, no. 17, pp. 2075–2085, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. A. B. Kornblith, J. E. Herndon II, L. R. Silverman et al., “Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a cancer and leukemia group B study,” Journal of Clinical Oncology, vol. 20, no. 10, pp. 2441–2452, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. J. M. Zingg and P. A. Jones, “Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis,” Carcinogenesis, vol. 18, no. 5, pp. 869–882, 1997. View at Publisher · View at Google Scholar · View at Scopus
  12. E. Li, “Chromatin modification and epigenetic reprogramming in mammalian development,” Nature Reviews Genetics, vol. 3, no. 9, pp. 662–673, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. M. J. Hoffmann and W. A. Schulz, “Causes and consequences of DNA hypomethylation in human cancer,” Biochemistry and Cell Biology, vol. 83, no. 3, pp. 296–321, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. P. W. Laird, L. Jackson-Grusby, A. Fazeli et al., “Suppression of intestinal neoplasia by DNA hypomethylation,” Cell, vol. 81, no. 2, pp. 197–205, 1995. View at Google Scholar · View at Scopus
  15. D. V. Santi, C. E. Garrett, and P. J. Barr, “On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs,” Cell, vol. 33, no. 1, pp. 9–10, 1983. View at Google Scholar · View at Scopus
  16. K. T. Lin, R. L. Momparler, and G. E. Rivard, “High-performance liquid chromatographic analysis of chemical stability of 5-aza-2'-deoxycytidine,” Journal of Pharmaceutical Sciences, vol. 70, no. 11, pp. 1228–1232, 1981. View at Google Scholar · View at Scopus
  17. R. E. Notari and J. L. DeYoung, “Kinetics and mechanisms of degradation of the antileukemic agent 5 azacytidine in aqueous solutions,” Journal of Pharmaceutical Sciences, vol. 64, no. 7, pp. 1148–1157, 1975. View at Google Scholar · View at Scopus
  18. S. M. Taylor and P. A. Jones, “Multiple new phenotypes induced in 10T 1/2 and 3T3 cells treated with 5-azacytidine,” Cell, vol. 17, no. 4, pp. 771–779, 1979. View at Google Scholar · View at Scopus
  19. J. P. J. Issa, G. Garcia-Manero, F. J. Giles et al., “Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2-deoxycytidine (decitabine) in hematopoietic malignancies,” Blood, vol. 103, no. 5, pp. 1635–1640, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. J. P. F. Issa, V. Gharibyan, J. Cortes et al., “Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate,” Journal of Clinical Oncology, vol. 23, no. 17, pp. 3948–3956, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. Z. Wang, D. R. Prudhomme, J. R. Buck, M. Park, and C. J. Rizzo, “Stereocontrolled syntheses of deoxyribonucleosides via photoinduced electron-transfer deoxygenation of benzoyl-protected ribo- and arabinonucleosides,” Journal of Organic Chemistry, vol. 65, no. 19, pp. 5969–5985, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. A. W. Johnson, G. W. Miller, J. A. Mills, and A. R. Todd, “Chemistry of the vitamin B12 group—part II. Synthesis of 5:6-Dimethyl-1-α-D-ribofuranosylbenziminazole,” Journal of the Chemical Society, pp. 3061–3066, 1953. View at Google Scholar · View at Scopus
  23. J. Phillips and A. Arena, “Optimization of Caco-2 Cell Growth and Differentiation for Drug Transport Studies,” Millipore Corporation Protocol Note PC1060EN00, 2003.
  24. I. Hubatsch, E. G. E. Ragnarsson, and P. Artursson, “Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers,” Nature Protocols, vol. 2, no. 9, pp. 2111–2119, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. K. K. Chan, D. D. Giannini, J. A. Staroscik, and W. Sadee, “5-Azacytidine hydrolysis kinetics measured by high-pressure liquid chromatography and 13C-NMR spectroscopy,” Journal of Pharmaceutical Sciences, vol. 68, no. 7, pp. 807–812, 1979. View at Google Scholar · View at Scopus
  26. P. Artursson and J. Karlsson, “Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (CACO-2) cells,” Biochemical and Biophysical Research Communications, vol. 175, no. 3, pp. 880–885, 1991. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Arena, J. Phillips, and M. Blanchard, “MultiScreen Caco-2 Assay System. Drug transport assays in a 96-well systemml: reproducibility and correlation to human absorption,” 2003, http://www.millipore.com/.
  28. P. Stenberg, U. Norinder, K. Luthman, and P. Artursson, “Experimental and computational screening models for the prediction of intestinal drug absorption,” Journal of Medicinal Chemistry, vol. 44, no. 12, pp. 1927–1937, 2001. View at Publisher · View at Google Scholar · View at Scopus
  29. R. L. Momparler, L. F. Momparler, and J. Samson, “Comparison of the antileukemic activity of 5-aza-2-deoxycytidine, 1-β-D-arabinofuranosylcytosine and 5-azacytidine against L1210 leukemia,” Leukemia Research, vol. 8, no. 6, pp. 1043–1049, 1984. View at Google Scholar · View at Scopus
  30. J. P. J. Issa and H. M. Kantarjian, “Targeting DNA methylation,” Clinical Cancer Research, vol. 15, no. 12, pp. 3938–3946, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. X. Yang, F. Lay, H. Han, and P. A. Jones, “Targeting DNA methylation for epigenetic therapy,” Trends in Pharmacological Sciences, vol. 31, no. 11, pp. 536–546, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. J. G. Herman, C. I. Civin, J. P. J. Issa, M. I. Collector, S. J. Sharkis, and S. B. Baylin, “Distinct patterns of inactivation of p15(INK4B) and p16(INK4A) characterize the major types of hematological malignancies,” Cancer Research, vol. 57, no. 5, pp. 837–841, 1997. View at Google Scholar · View at Scopus
  33. M. Lubbert, “Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?” Leukemia, vol. 17, no. 9, pp. 1762–1764, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. V. Santini, H. M. Kantarjian, and J. P. Issa, “Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications,” Annals of Internal Medicine, vol. 134, no. 7, pp. 573–586, 2001. View at Google Scholar · View at Scopus
  35. K. Raska, M. Jurovcik, Z. Sormova, and F. Sorm, “On the metabolism of 5-azacytidine and 5-aza-2-deoxycytidine in mice,” Collection of Czechoslovak Chemical Communications, vol. 30, pp. 3001–3006, 1965. View at Google Scholar
  36. C. J. Kelly, L. Gaudio, and D. W. Yesair, “Pharmacokinetic considerations in evaluating the effects of tetrahydrouridine on 5-azacytidine chemotherapy in L1210 leukemic mice,” Cancer Treatment Reports, vol. 62, no. 7, pp. 1025–1032, 1978. View at Google Scholar
  37. J. P. J. Issa, H. M. Kantarjian, and P. Kirkpatrick, “Azacitidine,” Nature Reviews Drug Discovery, vol. 4, no. 4, pp. 275–276, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. G. Garcia-Manero, M. L. Stoltz, M. R. Ward, H. Kantarjian, and S. Sharma, “A pilot pharmacokinetic study of oral azacitidine,” Leukemia, vol. 22, no. 9, pp. 1680–1684, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. G. Garcia-Manero, S. D. Gore, C. Cogle et al., “Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia,” Journal of Clinical Oncology, vol. 29, no. 18, pp. 2521–2527, 2011. View at Publisher · View at Google Scholar · View at PubMed
  40. H. M. Byun, S. H. Choi, P. W. Laird et al., “2-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: a novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1,” Cancer Letters, vol. 266, no. 2, pp. 238–248, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. M. Miwa, M. Ura, M. Nishida et al., “Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5 fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue,” European Journal of Cancer, vol. 34, no. 8, pp. 1274–1281, 1998. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Serova, C. M. Galmarini, A. Ghoul et al., “Antiproliferative effects of sapacitabine (CYC682), a novel 2-deoxycytidine-derivative, in human cancer cells,” British Journal of Cancer, vol. 97, no. 5, pp. 628–636, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. T. Delaunoit, P. A. Burch, J. M. Reid et al., “A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors,” Investigational New Drugs, vol. 24, no. 4, pp. 327–333, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. C. B. Yoo, S. Jeong, G. Egger et al., “Delivery of 5-aza-2-deoxycytidine to cells using oligodeoxynucleotides,” Cancer Research, vol. 67, no. 13, pp. 6400–6408, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. W. A. Creasey, M. E. Fink, R. E. Handschumacher, and P. Calabresi, “Clinical and pharmacological studies with 2,3,5-triacetyl-6-azauridine,” Cancer research, vol. 23, pp. 444–453, 1963. View at Google Scholar · View at Scopus
  46. M. Hidalgo, M. A. Villalona-Calero, S. G. Eckhardt et al., “Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies,” Journal of Clinical Oncology, vol. 18, no. 1, pp. 167–177, 2000. View at Google Scholar · View at Scopus
  47. P. Klivenyi, G. Gardian, N. Y. Calingasan et al., “Neuroprotective effects of oral administration of triacetyluridine against MPTP neurotoxicity,” NeuroMolecular Medicine, vol. 6, no. 2-3, pp. 87–92, 2004. View at Google Scholar · View at Scopus