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Preclinical and Clinical Studies on 5-Aza-2′-Deoxycytidine, a Potent Inhibitor of DNA Methylation, in Cancer Therapy

  • Richard L. Momparler
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Part of the Medical Intelligence Unit book series (MIUN)

Abstract

The preclinical and clinical investigations by the author on the antineoplastic activity of 5-Aza-2′-deoxycytidine (5AZA), a potent inhibitor of DNA methylation are reviewed. These include studies on the molecular, cellular and animal pharmacology of 5AZA. These preclinical studies indicated that 5AZA has enormous potential in cancer therapy. This potential is supported by reports in the literature indicate that 5AZA can reactivate many different types of genes that suppress tumorigenesis and were silenced by aberrant DNA me-thylation. However, the potential still remains to be demonstrated in clinical investigations where the author observed interesting responses in both patients with leukemia and lung can-cer. Several suggestions are made concerning the design of the optimal dose-schedule for 5AZA in cancer therapy. Preclinical studies show that 5AZA in combination with inhibitors of his-tone deacetylase (HDI) show a synergistic interaction against neoplastic cells. 5AZA plus HDI may have the potential to be a very effective chemotherapeutic regimen in patients with cancer.

Keywords

Acute Myeloid Leukemia Cytosine Arabinoside Cytidine Deaminase Antineoplastic Activity L1210 Leukemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Momparler RL, Chu MY, Fischer GA. Studies on a new mechanism of resistance of L5178Y murine leukemic cells to cytosine arabinoside. Biochem Biophys Acta 1968; 161:481–493.PubMedGoogle Scholar
  2. 2.
    Momparler RL, Fischer GA. Mammalian deoxynucleoside kinases. 1. Deoxycytidine kinase: Purification. Properties and kinetic studies with cytosine arabinoside. J Biol Chem 1968; 243:4398–4304.Google Scholar
  3. 3.
    Momparler RL. Effect of cytosine arabinoside 5′-triphosphate on mammalian DNA polymerase. Biochem Biophys Res Commun 1968; 34:465–471.CrossRefGoogle Scholar
  4. 4.
    Momparler RL. A model for the chemotherapy of acute leukemia with 1-β-arabinofuranosylcytosine. Cancer Res 1974; 34:1775–1787.PubMedGoogle Scholar
  5. 5.
    Sorm F, Vesely J. Effect of 5-aza-2 deoxycytidine against leukemic and hemopoietic tissues in AKR mice. Neoplasma 1968; 15:339.PubMedGoogle Scholar
  6. 6.
    Karon M, Sieger L, Leimbrock S et al. 5-Azacytidine: A new active agent for the treatment of acute leuekmia. Blood 1973; 42:359–365.PubMedGoogle Scholar
  7. 7.
    Momparler RL, Momparler RL, Samson J. Comparison of the antileukemic activity of 5-aza-2′-deoxycytidine, 1-β-D-arabinofuranosylcytosine and 5-azacytidine against L1210 leukemia. Leukemia Res 1984; 8:1043–1049.CrossRefGoogle Scholar
  8. 8.
    Momparler RL, Frith CH. Toxicology in mice of the antileukemic agent 5-aza-2′-deoxycytidine. Drug Chem Toxicology 1981; 4:373–381.Google Scholar
  9. 9.
    Momparler RL, Gonzales FA, Momparler LF et al. Preclinical evaluation of hematopoietic toxicity of antileukemic agent, 5-Aza-2′-deoxycytidine. Toxicology 1989; 57:329–336.PubMedCrossRefGoogle Scholar
  10. 10.
    Rivard GE, Momparler RL, Demers J et al. Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leukemia Res 1981; 5:453–462.CrossRefGoogle Scholar
  11. 11.
    Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2-deoxycytidine in patients with acute leukemia. Pharmac Ther 1986; 30:277–286.CrossRefGoogle Scholar
  12. 12.
    Momparler RL, Bouffard DY, Momparler LF et al. Pilot phase I-II study on 5-Aza-2′-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anticancer Drugs 1997; 8:358–368.PubMedCrossRefGoogle Scholar
  13. 13.
    Momparler RL, Ayou J. Potential of 5-aza-2′-deoxycytidine (Decitabine) a potent inhibitor of DNA methylation for therapy of advanced nonsmall lung cancer. Lung Cancer 2001; 334:S111–S115.CrossRefGoogle Scholar
  14. 14.
    Momparler RL. Molecular, cellular and animal pharmacology of 5-aza-2-deoxycytidine. Pharmac Ther 1986; 30:287–299.CrossRefGoogle Scholar
  15. 15.
    Pliml J, Sorm F. Synthesis of a deoxy-D-ribofuranosyl-5-cytosine. Collection Czech Chem Commun 1964; 29:2576–2577.Google Scholar
  16. 16.
    Lin KT, Momparler RL, Rivard GE. High performance liquid chromatographic analysis of chemical stability of 5-aza-2′-deoxycytidine. J Pharm Sci 1981; 70:1228–1232.PubMedCrossRefGoogle Scholar
  17. 17.
    Momparler RL, Derse D. Kinetics of phosphorylation of 5-aza-2′-deoxycytidine by deoxycytidine kinase. Biochem Pharmacol 1979; 28:1443–1444.PubMedCrossRefGoogle Scholar
  18. 18.
    Bouchard J, Momparle RL. Incorporation of 5-aza-2′-deoxycytidine 5′-triphosphate into DNA interactions with mammalian DNA polymerase and DNA methylase. Mol Pharmacol 1983; 24:109–114.PubMedGoogle Scholar
  19. 19.
    Chabo TG, Bouchard J, Momparler RL. 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 1983; 32:1327–1328.CrossRefGoogle Scholar
  20. 20.
    Momparler RL, Rossi M, Bouchard J. Kinetic interaction of 5-aza-2′-deoxycytidine 5′-monophosphate and its 5′-triphosphate with deoxycytidine deaminase. Mol Pharmacol 1984; 25:436–440.PubMedGoogle Scholar
  21. 21.
    Juttermann R, Li E, Jaenisch R. Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA 1994; 91:11797–11801.PubMedCrossRefGoogle Scholar
  22. 22.
    Momparler RL, Samson J, Momparler LF et al. Cell cycle effects and cellular pharmacology of 5-aza-2′-deoxycytidine. Cancer Chemotherapy Pharmacol 1984; 13:191–194.CrossRefGoogle Scholar
  23. 23.
    Bovenzi V, Momparler RL. Antineoplastic action of 5-aza-deoxycytidine and histone deacetylase inhibitor and thir effect on the expression of retinoic acid receptor a and estrogen receptor β genes in breast carcinoma cells. Cancer Chemother Pharmacol 2001; 71–76.Google Scholar
  24. 24.
    Primeau M, Gagnon J, Momparler RL. Synergistic antineoplastic action of DNA methylation inhibitor 5-aza-2′-deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells. Intl J Cancer 2003; 103:177–184.CrossRefGoogle Scholar
  25. 25.
    Momparler RL, Momparler LF. Chemotherapy of L1210 and L1210/ARA-C leukemia with 5-aza-2′-deoxycytidine and 3-deazauridine. Cancer Chemother and Phamacol 1980; 25:51–54.CrossRefGoogle Scholar
  26. 26.
    Eliolopoulos N, Momparler RL. Drug resistance to 5′-aza-2′-deoxycytidine, 2,2′-difluorodeoxycytidine and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol 1998; 42:373–378.CrossRefGoogle Scholar
  27. 27.
    Momparler RL, Onetto-Pothier N. Drug resistance to cytosine arabinoside. In: Kessel D, ed. Resistance to Antineoplastic Drugs. Boca Raton: CRC Press Inc., 1988:353–367.Google Scholar
  28. 28.
    Momparler RL, Gonzales FA. Effect of intravenous infusions of 5-aza-2′-deoxycytidine on survival time of mice with L1210 leukemia. Cancer Res 1978; 38:2673–2678.Google Scholar
  29. 29.
    Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2′-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res 1983; 43:349–3497.Google Scholar
  30. 30.
    Chabot G. Pharmacocinétique et effets antinéoplasiques de al 5-aza-2′-desoxycytidine chez les animaux. Ph.D. thesis. Université de Montréal 1983:166–174.Google Scholar
  31. 31.
    Momparler RL, Bouchard J, Onetto N. 5-Aza-2′-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation. Leukemia Res 1984; 8:181–185.CrossRefGoogle Scholar
  32. 32.
    Onetto N, Momparler RL, MomparleR LF et al. In vitro tests to evaluate the response to therapy of acute leukemia with cytosine arabinoside or 5-aza-deoxycytidine. Seminars Oncol 1987; 14:231–237.Google Scholar
  33. 33.
    Bender CM, Pao MM, Jones PA. Inhibition of DNA methylation by 5-aza-2′-deoxycytidine sup-presses the growth of tumor cell lines. Cancer Res 1998; 58:95–101.PubMedGoogle Scholar
  34. 34.
    Skipper HE, Shabel FM, Willcox WS. Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S phase specificity. Cancer Chemother Rep 1967; 51:125–165.PubMedGoogle Scholar
  35. 35.
    Momparler RL, Bovenzi V. DNA Methylation and Cancer (A Review) J. Cell Physiol 2000; 183:145–154.PubMedCrossRefGoogle Scholar
  36. 36.
    Momparler RL, Côté S, Eliopoulos N. Pharmacological approach for optimization of the dose-schedule of 5-Aza-2′-deoxycytidine (Decitabine) for the therapy of leukemia. Leukemia 1997; 11:175–180.PubMedCrossRefGoogle Scholar
  37. 37.
    Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980; 20:85–93.PubMedCrossRefGoogle Scholar
  38. 38.
    Pinto A, Attadia V, Fusco A et al. 5-Aza-2 deoxycytidine induces terminal differentiation of leuke-mic blasts from patients with acute myeloid leukemias. Blood 1984; 64:922–929.PubMedGoogle Scholar
  39. 39.
    Kreis W, Budman DR, Chan K et al. Therapy of refractory/relapsed leukemia with cytosine arabi-noside plus tetrahydrouridine (an inhibitor of cytidine deaminase)-a pilot study. Leukemia 1991:991–998.Google Scholar
  40. 40.
    Andreeff M, Goodrich DW, Pardee AB. Cell proliferation, differentiation and apoptosis. In: Bast RC, Kufe DW, Pollock RE et al. eds. Cancer Medicine, 5th ed. London: BC Decker Inc., 2000:17–20.Google Scholar
  41. 41.
    Weick JK, Kepecky KJ, Appelbaum FR et al. A randomized investigation of high dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group study. Blood 1996; 88:2841–2851.PubMedGoogle Scholar
  42. 42.
    Dobrovic A, Simplefendorfer D. Methylation of the BRACl gene in sporadic breast cancer. Cancer Res 1997; 57:3347–3350.PubMedGoogle Scholar
  43. 43.
    Ganser A, Heil G. Use of hematopoietic growth factors in the treatment of aclute myelogenous leukemia. Curr Opin Hematol 1997; 4:191–195.PubMedCrossRefGoogle Scholar
  44. 44.
    Cameron EE, Bachman KE, Myohanen S et al. Synergy of demethylation and histone deacetylase inhibition in the reexpression of genes silenced in cancer. Nat Genet 1999; 21:103–112.PubMedCrossRefGoogle Scholar
  45. 45.
    Marks PA, Rifkind RA, Richon VM et al. Histone deacetylases and cancer: Causes and therapies. Nature Reviews 2001; 1:194–202.PubMedCrossRefGoogle Scholar
  46. 46.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nature Rev 2002; 415–428.Google Scholar
  47. 47.
    Bovin A-J, Momparler LF, Hurtubise A et al. Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung cancer. Anti-Cancer Drugs 2002; 13:1–6.CrossRefGoogle Scholar
  48. 48.
    Shaker S, Bernstein M, Momparler LF et al. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2′-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) against myeloid leukemic cells. Leukemia Res 2003 in pressx.Google Scholar
  49. 49.
    Côté S, Momparler RL. Antineoplastic action of all-trans retinoic acid and 5-aza-2′-deoxycytidine on human DLD-1 colon carcinoma cells. Cellular Pharmacol 1995; 2:221–228.Google Scholar
  50. 50.
    Côté S, Sinnett D, Momparler RL. Demethylation by 5′-aza-2′-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor beta gene in human colon carcinoma cells. Anti-Cancer Drugs 1998; 9:743–750.PubMedCrossRefGoogle Scholar
  51. 51.
    Momparler RL, Vesely J, Momparler LF et al. Synergistic action of 5-aza-2′-deoxycytidine and 3-deazauridine on L1210 leukemic cells and EMT tumor cells. Cancer Res 1979; 39:3822–3827.PubMedGoogle Scholar
  52. 52.
    Bouffard DY, Momparler LF, Momparler RL. Enhancement of the antileukemic activity of 5-aza-2′-deoxycytidine by cyclopentenyl cytosine in HL-60 leukemic cell line. Anti-Cancer Drugs 1994; 5:223–228.PubMedCrossRefGoogle Scholar
  53. 53.
    MacLeod AR, Szyf M. Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem 1995; 270:8037–8043.PubMedCrossRefGoogle Scholar
  54. 54.
    Braakhius BJM, van Dongen GAMS, van Walsum M et al. Preclinical antitumor activity of 5-aza-2′-deoxycytidine against human head and neck cancer xenografts. Invest New Drugs 1988; 6:299–304.Google Scholar
  55. 55.
    Richel DJ, Colly LP, Kluin-Nelemans JC et al. The antileukaemic activity of 5-aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia. Br J Cancer 1991; 64:144–149.PubMedGoogle Scholar
  56. 56.
    Pinto A, Zagonel V. 5-Aza-2 deoxycytidine (Decitabine) and 5-azacytidine in the treatment of acute myeloid leukemias and myelodysplastic syndrome: Past, present and future trends. Leukemia 1993; 7(suppl 1):51–60.PubMedGoogle Scholar
  57. 57.
    Kantarjian HM, O’Brien SM, Keating M et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 1997; 11:1617–1620.PubMedCrossRefGoogle Scholar
  58. 58.
    Daskalakis M, Nguyen TT, Nguyen C et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2 deoxycytidine (Decitabine) treatment. Blood 2002; 100:2957–2964.PubMedCrossRefGoogle Scholar
  59. 59.
    Weber J, Salgaller M, Samid D et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2 deoxycytidine. Cancer Res 1994; 54:1766–1771.PubMedGoogle Scholar
  60. 60.
    Coral S, Sigalotti L, Gasparollo A et al. Prolonged upregultation of the expression of HLA Class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2 deoxycytidine (5-AZA-CdR). J Immunother 1999; 22:16–24.PubMedCrossRefGoogle Scholar
  61. 61.
    Weiser TS, Sheng Guo Z, Ohnmacht GA et al. Sequential 5-aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ES0-1. J Immunother 2001; 24:151–161.CrossRefGoogle Scholar
  62. 62.
    Sigalotte L, Coral S, Nardi G et al. Promoter methylation controls the expression of MAGE2,3, and 4 genes in human cutaneous melanoma. J Immumother 2002; 28:16–26.CrossRefGoogle Scholar
  63. 63.
    Zaharko DS, Covey JM, Muneses CC. Experimental chemotherapy (L1210) with 5-aza-2 deoxycytidine in combination with pyran copolymer (MVE-4) as immune adjuvant. J Natl Cancer Inst 1985; 74:1319–1324.PubMedGoogle Scholar

Copyright information

© Eurekah.com and Kluwer Academic/Plenum Publishers 2005

Authors and Affiliations

  • Richard L. Momparler
    • 1
  1. 1.Department de PharmacologieUniversity de Montreal, Centre de Recherche, Hosptial Sainte-JustineMontrealCanada

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