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5-Azacytidine/5-Azacitidine

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Small Molecules in Oncology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 201))

Abstract

The hypomethylating agent 5-Azacytidine epigenetically modulates various genes, including tumor suppressor genes. For many years, the “new agent”, which was first discovered in the 1960s, remained fairly unobtrusive in the rank of salvage treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). When the significance of epigenetics in tumorigenesis became clear, 5-Azacytidine attracted new attention. Finally, it was the first drug approved for the treatment of all categories of MDS, and its survival benefit over best conventional care was confirmed. Today, in many clinical situations, when aggressive therapies including allogeneic hematopoietic cell transplantation are not an option, 5-Azacytidine is the first treatment of choice. Preliminary data on combinations of the hypomethylating agent with other new drugs are promising, and innovative strategies involving immune modulation and regenerative tissue repair hold a broad potential for future developments.

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References

  • Adès L, Sekeres MA, Wolfromm A, Teichman ML, Tiu RV, Itzykson R, Maciejewski JP, Dreyfus F, List AF, Fenaux P, Komrokji RS (2013) Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 37:609–613

    Article  PubMed  Google Scholar 

  • Al-Ali HK, Jaekel N, Junghanss C, Maschmeyer G, Krahl R, Cross M, Hoppe G, Niederwieser D (2012) Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 53:110–117

    Article  CAS  PubMed  Google Scholar 

  • Aoki E, Uchida T, Ohashi H, Nagai H, Murase T, Ichikawa A, Yamao K, Hotta T, Kinoshita T, Saito H, Murate T (2000) Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes. Leukemia 14:586–593

    Article  CAS  PubMed  Google Scholar 

  • Bally C, Thépot S, Quesnel B, Vey N, Dreyfus F, Fadlallah J, Turlure P, de Botton S, Dartigeas C, de Renzis B, Itzykson R, Fenaux P, Adès L (2013) Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res 37:637–640

    Article  CAS  PubMed  Google Scholar 

  • Bellet RE, Mastrangelo MJ, Engstrom PF, Custer RP (1973) Hepatotoxicity of 5-azacytidine (NSC-102816) (a clinical and pathologic study). Neoplasma 20:303–309

    CAS  PubMed  Google Scholar 

  • Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199

    Article  CAS  PubMed  Google Scholar 

  • Bergy ME, Herr RR (1966) Microbiological production of 5-azacytidine. II. Isolation and chemical structure. Antimicrob Agents Chemother (Bethesda) 6:625–630

    CAS  Google Scholar 

  • Bird AP (1996) The relationship of DNA methylation to cancer. Cancer Surv 28:87–101

    CAS  PubMed  Google Scholar 

  • Borthakur G, Huang X, Kantarjian H, Faderl S, Ravandi F, Ferrajoli A, Torma R, Morris G, Berry D, Issa JP (2010) Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes. Leuk Lymphoma 51:73–78

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chabot GG, Bouchard J, Momparler RL (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

    Article  CAS  PubMed  Google Scholar 

  • Chim CS, Pang R, Fung TK, Choi CL, Liang R (2007) Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma. Leukemia 21:2527–2536

    Article  CAS  PubMed  Google Scholar 

  • Chiurazzi P, Pomponi MG, Pietrobono R, Bakker CE, Neri G, Oostra BA (1999) Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum Mol Genet 8:2317–2323

    Article  CAS  PubMed  Google Scholar 

  • Choi SH, Byun HM, Kwan JM, Issa JP, Yang AS (2007) Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition. Br J Haematol 138:616–623

    Article  CAS  PubMed  Google Scholar 

  • Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E, Piwnica-Worms DR, DiPersio JF (2010) In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 116:129–139

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Christiansen DH, Andersen MK, Pedersen-Bjergaard J (2003) Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 17:1813–1819

    Article  CAS  PubMed  Google Scholar 

  • Costa R, Abdulhaq H, Haq B, Shadduck RK, Latsko J, Zenati M, Atem FD, Rossetti JM, Sahovic EA, Lister J (2011) Activity of azacitidine in chronic myelomonocytic leukemia. Cancer 117:2690–2696

    Article  CAS  PubMed  Google Scholar 

  • Creusot F, Acs G, Christman JK (1982) Inhibition of DNA methyltransferase and induction of friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2′-deoxycytidine. J Biol Chem 257:2041–2048

    CAS  PubMed  Google Scholar 

  • De Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G (2010) Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 116:5420–5431

    Article  PubMed  Google Scholar 

  • Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini JL, de Botton S, Fenaux P, Kroemer G (2008) A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts. Cell Cycle 7:2139–2145

    Article  CAS  PubMed  Google Scholar 

  • Fenaux P, Ades L (2009) Review of azacitidine trials in intermediate-2-and high-risk myelodysplastic syndromes. Leuk Res 33(Suppl 2):S7–11

    Article  CAS  PubMed  Google Scholar 

  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR (2009) International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10:223–232

    Article  CAS  PubMed  Google Scholar 

  • Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR (2010a) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569

    Article  CAS  PubMed  Google Scholar 

  • Fenaux P, Gattermann N, Seymour JF, Hellström-Lindberg E, Mufti GJ, Duehrsen U, Gore SD, Ramos F, Beyne-Rauzy O, List A, McKenzie D, Backstrom J, Beach CL (2010b) Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol 149:244–249

    Article  CAS  PubMed  Google Scholar 

  • Fianchi L, Criscuolo M, Lunghi M, Gaidano G, Breccia M, Levis A, Finelli C, Santini V, Musto P, Oliva EN, Leoni P, Aloe Spiriti A, D’Alò F, Hohaus S, Pagano L, Leone G, Voso MT (2012) Outcome of therapy-related myeloid neoplasms treated with azacitidine. J Hematol Oncol 5:44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5:e38

    Article  PubMed Central  PubMed  Google Scholar 

  • Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, Laille E, Giordano H, Sakoian S, Jabbour E, Kantarjian H, Skikne B (2011) Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol 29:2521–2527

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gore SD, Fenaux P, Santini V, Bennett JM, Silverman LR, Seymour JF, Hellström-Lindberg E, Swern AS, Beach CL, List AF (2013) A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 98:1067–1072

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Griffiths EA, Gore SD (2008) DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol 45:23–30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E (2010) Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol 150:293–302

    Article  PubMed  Google Scholar 

  • Gurion R, Vidal L, Gafter-Gvili A, Belnik Y, Yeshurun M, Raanani P, Shpilberg O (2010) 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome—a systematic review and meta-analysis. Haematologica 95:303–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hanka LJ, Evans JS, Mason DJ, Dietz A (1966) Microbiological production of 5-azacytidine. I. Production and biological activity. Antimicrob Agents Chemother (Bethesda) 6:619–624

    CAS  Google Scholar 

  • Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    Article  CAS  PubMed  Google Scholar 

  • Israili ZH, Vogler WR, Mingioli ES, Pirkle JL, Smithwick RW, Goldstein JH (1976) The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion. Cancer Res 36:1453–1461

    CAS  PubMed  Google Scholar 

  • Itzykson R, Thépot S, Fabre C, Dreyfus F, Quesnel B, Wattel E, de Botton S, Pilorge S, Dartigeas C, Stamatoullas A, Prebet T, Ojeda-Uribe M, Cheze S, Tournilhac O, Solary E, Damaj G, Tertian G, Himberlin C, Mbida RM, Beve B, Adès L, Gardin C, Fenaux P (2008) Response to azacytidine (AZA) in MDS or AML with Del 5q: current results of the french ATU program. Blood 112:2682 (abstract)

    Google Scholar 

  • Jawad M, Russell NH, Pallis M (2008) Azacytidine and gemtuzumab ozogamicin co-operate to inhibit the Wnt pathway and increase cytotoxicity in AML. Blood 112:2991 (abstract)

    Google Scholar 

  • Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20:85–93

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Taylor SM (1981) Hemimethylated duplex DNAs prepared from 5-azacytidine-treated cells. Nucleic Acids Res 9:2933–2947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, Leighton JK, Patel H, Rahman A, Sridhara R, Wang YC, Pazdur R (2005a) Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11:3604–3608

    Article  CAS  PubMed  Google Scholar 

  • Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R (2005b) FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10:176–182

    Article  CAS  PubMed  Google Scholar 

  • Kornblith AB, Herndon JE 2nd, Silverman LR, Demakos EP, Odchimar-Reissig R, Holland JF, Powell BL, DeCastro C, Ellerton J, Larson RA, Schiffer CA, Holland JC (2002) 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. J Clin Oncol 20:2441–2452

    Article  CAS  PubMed  Google Scholar 

  • Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U, Gattermann N (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266–1269

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, List AF, Hozo I, Komrokji R, Djulbegovic B (2010) Decitabine versus 5-azacitidine for the treatment of myelodysplastic syndrome: adjusted indirect meta-analysis. Haematologica 95:340–342

    Article  PubMed Central  PubMed  Google Scholar 

  • Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL, Mineur P, Bennett JM, Berger MS, Eten CB, Munteanu M, Loken MR, Van Dongen JJ, Bernstein ID, Appelbaum FR (2002) Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia 16:1627–1636

    Article  CAS  PubMed  Google Scholar 

  • Lee YG, Kim I, Yoon SS, Park S, Cheong JW, Min YH, Lee JO, Bang SM, Yi HG, Kim CS, Park Y, Kim BS, Mun YC, Seong CM, Park J, Lee JH, Kim SY, Lee HG, Kim YK, Kim HJ; Korean Society of Haematology AML/MDS working party (2013) Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 161:339-347

    Google Scholar 

  • Li LH, Olin EJ, Buskirk HH, Reineke LM (1970a) Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 30:2760–2769

    CAS  PubMed  Google Scholar 

  • Li LH, Olin EJ, Fraser TJ, Bhuyan BK (1970b) Phase specifi city of 5-azacytidine against mammalian cells in tissue culture. Cancer Res 30:2770–2775

    CAS  PubMed  Google Scholar 

  • Lin J, Gilbert J, Rudek MA, Zwiebel JA, Gore S, Jiemjit A, Zhao M, Baker SD, Ambinder RF, Herman JG, Donehower RC, Carducci MA (2009) A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res 15:6241–6249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lomen PL, Baker LH, Neil GL, Samson MK (1975) Phase I study of 5-azacytidine (NSC-102816) using 24-hour continuous infusion for 5 days. Cancer Chemother Rep 59:1123–1126

    CAS  PubMed  Google Scholar 

  • Lyons RM, Cosgriff TM, Modi SS, Gersh RH, Hainsworth JD, Cohn AL, McIntyre HJ, Fernando IJ, Backstrom JT, Beach CL (2009) Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 27:1850–1856

    Article  CAS  PubMed  Google Scholar 

  • Marcucci G, Silverman L, Eller M, Lintz L, Beach CL (2005) Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 45:597–602

    Article  CAS  PubMed  Google Scholar 

  • Martin MG, Walgren RA, Procknow E, Uy GL, Stockerl-Goldstein K, Cashen AF, Westervelt P, Abboud CN, Kreisel F, Augustin K, Dipersio JF, Vij R (2009) A phase II study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes. Am J Hematol 84:560–564

    Article  CAS  PubMed  Google Scholar 

  • Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, Lunghi M, D’Arco AM, Levis A, Pastore D, Di Renzo N, Santagostino A, Pavone V, Buccisano F, Musto P (2012) Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer 118:1014–1022

    Article  CAS  PubMed  Google Scholar 

  • Mesa RA, Verstovsek S, Rivera C, Pardanani A, Hussein K, Lasho T, Wu W, Tefferi A (2009) 5-Azacitidine has limited therapeutic activity in myelofibrosis. Leukemia 23:180–182

    Article  CAS  PubMed  Google Scholar 

  • Nagar M, Vernitsky H, Cohen Y, Dominissini D, Berkun Y, Rechavi G, Amariglio N, Goldstein I (2008) Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells. Int Immunol 20:1041–1055

    Article  CAS  PubMed  Google Scholar 

  • Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P (2008) Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma 49:2141–2147

    Article  CAS  PubMed  Google Scholar 

  • Orazi A, Germing U (2008) The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22:1308–1319

    Article  CAS  PubMed  Google Scholar 

  • Platzbecker U, Schetelig J, Finke J, Trenschel R, Scott BL, Kobbe G, Schaefer-Eckart K, Bornhäuser M, Itzykson R, Germing U, Beelen D, Ehninger G, Fenaux P, Deeg HJ, Adès L; German MDS Study; Cooperative Transplant Study Group; Fred Hutchinson Cancer Research Center; Groupe Francophone des Myelodysplasies (2012a) Allogeneic hematopoietic cell transplantation in patients age 60–70 years with de novo high-risk myelodysplastic syndrome or secondary acute myelogenous leukemia: comparison with patients lacking donors who received azacitidine. Biol Blood Marrow Transplant 18:1415-1421

    Google Scholar 

  • Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, Klut IM, Knoth H, Röllig C, Schetelig J, Mohr B, Graehlert X, Ehninger G, Bornhäuser M, Thiede C (2012) Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 26:381–389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654–1663

    Article  CAS  PubMed  Google Scholar 

  • Pollyea DA, Kohrt HE, Gallegos L, Figueroa ME, Abdel-Wahab O, Zhang B, Bhattacharya S, Zehnder J, Liedtke M, Gotlib JR, Coutre S, Berube C, Melnick A, Levine R, Mitchell BS, Medeiros BC (2012) Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 26:893–901

    Article  CAS  PubMed  Google Scholar 

  • Presant CA, Vietti T, Valeriote F (1975) Kinetics of both leukemic and normal cell population reduction following 5-azacytidine. Cancer Res 35:1926–1930

    CAS  PubMed  Google Scholar 

  • Quintás-Cardama A, Tong W, Kantarjian H, Thomas D, Ravandi F, Kornblau S, Manshouri T, Cortes JE, Garcia-Manero G, Verstovsek S (2008) A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia 22:965–970

    Article  PubMed  Google Scholar 

  • Quintás-Cardama A, Ravandi F, Liu-Dumlao T, Brandt M, Faderl S, Pierce S, Borthakur G, Garcia-Manero G, Cortes J, Kantarjian H (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120:4840–4845

    Article  PubMed Central  PubMed  Google Scholar 

  • Raffoux E, Cras A, Recher C, Boëlle PY, de Labarthe A, Turlure P, Marolleau JP, Reman O, Gardin C, Victor M, Maury S, Rousselot P, Malfuson JV, Maarek O, Daniel MT, Fenaux P, Degos L, Chomienne C, Chevret S, Dombret H (2010) Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget 1:34–42

    PubMed  Google Scholar 

  • Ramsingh G, Westervelt P, Cashen AF, Uy GL, Stockerl-Goldstein K, Abboud CN, Bernabe N, Monahan R, DiPersio JF, Vij R (2013) A phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AML. Leukemia 27:725–728

    Article  CAS  PubMed  Google Scholar 

  • Ravandi F, Issa JP, Garcia-Manero G, O’Brien S, Pierce S, Shan J, Borthakur G, Verstovsek S, Faderl S, Cortes J, Kantarjian H (2009) Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 115:5746–5751

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M (2013) Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 121:4655–4662

    Article  CAS  PubMed  Google Scholar 

  • Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF (2008) Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111:86–93

    Article  CAS  PubMed  Google Scholar 

  • Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, Giagounidis A, Zohren F, Bruns I, Wolschke C, Rieger K, Fenk R, Germing U, Haas R, Kröger N, Kobbe G (2013) Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 27:1229–1235

    Article  CAS  PubMed  Google Scholar 

  • Scott BL, Ramakrishnan A, Storer B, Becker PS, Petersdorf S, Estey EH, Deeg HJ (2010) Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol 148:944–947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R, Raza A, List AF (2008) Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 26:5943–5949

    Article  PubMed Central  PubMed  Google Scholar 

  • Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D, Paulic K, Afable M, Saba HI, Loughran TP Jr, Maciejewski JP (2010) Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 28:2253–2258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sekeres MA, O’Keefe C, List AF, Paulic K, Afable M 2nd, Englehaupt R, Maciejewski JP (2011) Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol 86:102–103

    Article  PubMed  Google Scholar 

  • Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M, Englehaupt R, Juersivich J, Cuthbertson D, Paleveda J, Tabarroki A, Visconte V, Makishima H, Jerez A, Paquette R, List AF, Maciejewski JP (2012) Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 120:4945–4951

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Seymour JF, Fenaux P, Silverman LR, Mufti GJ, Hellström-Lindberg E, Santini V, List AF, Gore SD, Backstrom J, McKenzie D, Beach CL (2010) Effects of azacitidine compared with conventional care regimens in elderly (≥ 75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol 76:218–227

    Article  PubMed  Google Scholar 

  • Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19:3244–3254

    CAS  PubMed  Google Scholar 

  • Silverman LR (2001) Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist 6(Suppl 5):8–14

    Article  CAS  PubMed  Google Scholar 

  • Silverman LR, Holland JF, Weinberg RS, Alter BP, Davis RB, Ellison RR, Demakos EP, Cornell CJ Jr, Carey RW, Schiffer C et al (1993) Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7(Suppl 1):21–29

    PubMed  Google Scholar 

  • Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440

    Article  CAS  PubMed  Google Scholar 

  • Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, Larson RA (2006) Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the cancer and leukemia group B. J Clin Oncol 24:3895–3903

    Article  CAS  PubMed  Google Scholar 

  • Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellström-Lindberg E, Gattermann N, Sanz G, List AF, Gore SD, Seymour JF, Backstrom J, McKenzie D, Beach CL (2008a) The effects of continued azacitidine (AZA) treatment cycles on response in higher-risk patients (Pts) with myelodysplastic syndromes (MDS). Blood 112:227 (abstract)

    Google Scholar 

  • Silverman LR, Verma A, Odchimar-Reissig R, LeBlanc A, Najfeld V, Gabrilove J, Isola L, Espinoza-Delgado I, Zwiebel J (2008b) A phase I trial of the epigenetic modulators vorinostat, in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): a study of the New York cancer consortium. Blood 112:3656 (abstract)

    Google Scholar 

  • Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellström-Lindberg E, Gattermann N, Sanz G, List AF, Gore SD, Seymour JF (2011) Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 117:2697–2702

    Article  CAS  PubMed  Google Scholar 

  • Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G (2007) Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110:2302–2308

    Article  CAS  PubMed  Google Scholar 

  • Sorm F, Vesely J (1964) The activity of a new antimetabolite, 5-azacytidine, against lymphoid leukaemia in Ak mice. Neoplasma 11:123–130

    CAS  PubMed  Google Scholar 

  • Sorm F, Piskala A, Cihak A, Vesely J (1964) 5-Azacytidine, a new, highly effective cancerostatic. Experientia 20:202–203

    Article  CAS  PubMed  Google Scholar 

  • Stamatoyannopoulos JA (1992) Future prospects for treatment of hemoglobinopathies. West J Med 157:631–636

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123:8–13

    Article  CAS  PubMed  Google Scholar 

  • Taylor SM, Jones PA (1982) Mechanism of action of eukaryotic DNA methyltransferase. Use of 5-azacytosine-containing DNA. J Mol Biol 162:679–692

    Article  CAS  PubMed  Google Scholar 

  • Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, Sorin L, Dreyfus F, Cluzeau T, Delaunay J, Sanhes L, Eclache V, Dartigeas C, Turlure P, Harel S, Salanoubat C, Kiladjian JJ, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies (GFM) (2010) Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 116:3735-3742

    Google Scholar 

  • Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T, Murate T (1997) Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403–1409

    CAS  PubMed  Google Scholar 

  • van der Helm LH, Alhan C, Wijermans PW, van Marwijk Kooy M, Schaafsma R, Biemond BJ, Beeker A, Hoogendoorn M, van Rees BP, de Weerdt O, Wegman J, Libourel WJ, Luykx-de Bakker SA, Minnema MC, Brouwer RE, Croon-de Boer F, Eefting M, Jie KS, van de Loosdrecht AA, Koedam J, Veeger NJ, Vellenga E, Huls G (2011) Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. Br J Haematol 155:599–606

    Article  PubMed  Google Scholar 

  • Vogler WR, Miller DS, Keller JW (1976) 5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. Blood 48:331–337

    CAS  PubMed  Google Scholar 

  • von Hoff DD, Slavik M (1977) 5-azacytidine—a new anticancer drug with significant activity in acute myeloblastic leukemia. Adv Pharmacol Chemother 14:285–326

    Article  Google Scholar 

  • von Hoff DD, Slavik M, Muggia FM (1976) 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 85:237–245

    Article  Google Scholar 

  • Voso MT, Santini V, Finelli C, Musto P, Pogliani E, Angelucci E, Fioritoni G, Alimena G, Maurillo L, Cortelezzi A, Buccisano F, Gobbi M, Borin L, Di Tucci A, Zini G, Petti MC, Martinelli G, Fabiani E, Fazi P, Vignetti M, Piciocchi A, Liso V, Amadori S, Leone G (2009) Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 15:5002–5007

    Article  CAS  PubMed  Google Scholar 

  • Xing Y, Lv A, Wang L, Yan X (2012) The combination of angiotensin II and 5-azacytidine promotes cardiomyocyte differentiation of rat bone marrow mesenchymal stem cells. Mol Cell Biochem 360:279–287

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland

    Antonia M. S. Müller

  2. Division of Blood and Marrow Transplantation, Stanford University, Stanford, USA

    Mareike Florek

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Correspondence to Antonia M. S. Müller .

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  1. Cancer Center Heilbronn-Franken, SLK-Kliniken Heilbronn GmbH Medizinische Klinik III, Heilbronn, Germany

    Uwe M. Martens

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Müller, A.M.S., Florek, M. (2014). 5-Azacytidine/5-Azacitidine. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54490-3_19

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