Abstract
Besides 5-azacytidine (azacitidine, Vidaza®), 5-aza-2′-deoxycytidine (decitabine, Dacogen®) is the most widely used inhibitor of DNA methylation, which triggers demethylation leading to consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although antileukemic activity of decitabine is known for almost 40 years, its therapeutic potential in hematologic malignancies has only recently led to its approval in higher-risk MDS patients and as first-line treatment in AML patients >65 years who are not candidates for intensive chemotherapy. Several clinical trials showed promising activity of low-dose decitabine also in CML and hemoglobinopathies, whereas its efficacy in solid tumors is very limited. Clinical responses appear to be exerted both by epigenetic alterations and by induction of cell-cycle arrest and/or apoptosis. Recent and ongoing clinical trials investigate new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase inhibitors.
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References
Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jäger E, Lübbert M (2010) The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res 34:899–905
Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schätzlein A, Twelves C, Kaye SB, 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
Baylin SB, Herman JG, Vertino PM, Issa JP (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Cancer Res 72:141–196
Baylin SB (2002) Mechanisms underlying epigenetically mediated gene silencing in cancer. Semin Cancer Biol 12:331–337
Bhalla KN (2005) Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol 23:3971–3993
Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884–3891
Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G (2010) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 107:7473–7478
Bodey B (2002) Cancer-testis antigens: promising targets for antigen directed antineoplastic immunotherapy. Expert Opin Biol Ther 2:577–584
Bogani C, Ponziani V, Guglielmelli P, Desterke C, Rosti V, Bosi A, Le Bousse-Kerdiles MC, Barosi G, Vannucchi AM (2008) Hypermethylation of CXCR4 promotor in CD34+ cells from patients with primary myelofibrosis. Stem Cells 26:1920–1930
Boivin AJ, Momparler LF, Hurtubise A, Momparler RL (2002) Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells. Anticancer Drugs 13:869–874
Borthakur G, Ahdab SE, Ravandi F, Faderl S, Ferrajoli A, Newman B, Issa JP, Katarjian H (2008) Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma 49:690–695
Calabro L, Fonsatti E, Altomonte M, Pezzani L, Colizzi F, Nanni P, Gattei V, Sigalotti L, Maio M (2005) Methylation-regulated expression of cancer testis antigens in primary effusion lymphoma: immunotherapeutic implications. J Cell Physiol 202:474–477
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103–107
Cashen AF, Shah AK, Todt L, Fisher N, DiPersio J (2008) Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Cancer Chemother Pharmacol 61:759–766
Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF (2010) Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556–561
Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE, Jones PA, Selker EU (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95:399–409
Cheng JC, Weisenberger DJ, Gonzales FA, Liang G, Xu GL, Hu YG, Marquez VE, Jones PA (2004) Continuous zebularine treatment effectively sustains demethylation in human bladder cancer cells. Mol Cell Biol 24:1270–1278
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
Coral S, Sigalotti L, Altomonte M, Engelsberg A, Colizzi F, Cattarossi I, Maraskovsky E, Jager E, Seliger B, Maio M (2002) 5-aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell caricoma: immunotherapeutic implications. Cancer Res 8:2690–2695
Coral S, Sigalotti L, Colizzi F, Spessotto A, Nardi G, Cortini E, Pezzani L, Fratta E, Fonsatti E, Di Giacomo AM, Nicotra MR, Natali PG, Altomonte M, Maio M (2006) Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications. J Cell Physiol 207:58–66
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
Danilov AV, Relias V, Feeney DM, Miller KB (2009) Decitabine is an effective treatment of idiopathic meylofibrosis (Correspondence). Brit J Haematol 145:131–132
Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Kohler G, Wijermans P, Jones PA, Lübbert 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
Debusscher L, Marie JP, Dodion P, Blanc GM, Arrigo C, Zittoun R, Stryckmans P (1990) Phase-I-II trial of 5-aza-2′-deoxycytidine in adult patients with acute leukemia. In: Momparler RL, de Vos D (eds) 5-Aza-2′-deoxycytidine: preclinical and clinical studies. PCH, Haarlem, The Netherlands, pp 131–142
De Lima M, Ravandi F, Shahjahan M, Andersson B, Couriel D, Donato M, Khouri I, Gajewski J, van Besien K, Champlin R, Giralt S, Kantarjian H (2003) Long-term follow up of a phase I study of high-dose Decitabine, Busulfan, and Cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias. Cancer 97:1242–1247
De Padua Silva L, de Lima M, Kantarjian H, Faderl S, Kebriaei P, Giralt S, Davisson J, Garcia-Manero G, Champlin R, Issa J-P, Ravandi F (2009) Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome. Bone Marrow Transplant 43:839–843
DeSimone J, Koshy M, Dorn L, Lavelle D, Bressler L, Molokie R, Talischy N (2002) Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99:3905–3908
Smet De, Lurquin C, Lethe B, Martelange V, Boon T (1999) DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol 19:7327–7335
D’Incalci M, Covey JM, Zaharko DS, Kohn KW (1985) DNA alkali-labile sites induced by incorporation of 5-aza-2′-deoxycytidine into DNA of mouse leukemia L1210 cells. Cancer Res 45:3197–3202
Dodion PF, Clavel M, ten Bokkel Huinink W, Robinson E, Renard JF (1990) Phase-II trials with 2′-deoxy-5-azacytidine conducted by the Early Clinical Trials group of the EORTC. In: Momparler RL, de Vos D (eds) 5-Aza-2′-deoxycytidine: preclinical and clinical studies. PCH, Haarlem, The Netherlands, pp 117–124
Driscoll JS, Marquez VE, Plowman J, Liu PS, Kelley JA, Barchi JJ Jr (1991) Antitumor properties of 2(1H)-pyrimidinone riboside (zebularine) and its fluorinated analogues. J Med Chem 34:3280–3284
Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159
Fathallah H, Atweh GF (2006) DNA hypomethylation therapy for hemoglobin disorders: molecular mechanisms and clinical application. Blood Rev 20:227–234
Fathallah H (2008) DNA hypomethylation therapies and hemoglobin disorders. [An interview with Hassana Fathallah by H&O]. Clin Adv Hematol Oncol 6:806–808
Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R, Wang Y, Balusu R, Chen J, Koul S, Joshi A, Upadhyay S, Atadja P, Bhalla KN (2009) Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 8:939–950
Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, Plass C, Niemeyer CM, Lübbert M (2009) The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 23:1019–1028
Garcia-Manero G, Jeha S, Daniel J, Williamson J, Albitar M, Kantarjian HM, Issa JP (2003) Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer 3:695–702
Garcia-Manero G, Issa JP (2005) Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents. Cancer Invest 23:635–642
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279
Garcia-Manero G, Yang H, Kuang SQ, O’Brien S, Thomas D, Kantarjian H (2009) Epigenetics of acute lymphocytic leukemia. Semin Hematol 46:24–32
Gattei V, Fonsatti E, Sigalotti L, Degan M, Di Giacomo AM, Altomonte M, Calabro L, Maio M (2005) Epigenetic immunomodulation of hematopoietic malignancies. Semin Oncol 32:503–510
Giralt S, Davis M, O’Brien S, Van Besien K, Champlin R, De Vos D, Kantarjian H (1997) Studies of decitabine with allogeneic progenitor cell transplantation. Leukemia 11(Suppl 1):32–34
Giralt S, Cohen A, Davis M, O’Brien S, Andersson B, Gajewski J, Khouri I, Körbling M, Champlin R, De Vos D, Kantarjian H (1998a) Phase-I/II study of decitabine with allogeneic peripheral blood stem cell transplantation for treatment of relapse after allogeneic progenitor cell transplantation. In: Symposium on methyltransferase inhibitors in hematologic malignancies, Miami, FL, Dec 1998 (abstract)
Giralt S, Cohen A, Davis M, O’Brien S, Andersson B, Gajewski J, Khouri I, Körbling M, Champlin R, de Vos D, Kantarjian H (1998b) Phase-I/II trial combining decitabine with busulfan/cyclophosphamide as a conditioning regimen for allogeneic progenitor cell transplantation. In: Symposium on methyltransferase inhibitors in hematologic malignancies, Miami, Dec 1998 (abstract)
Gollob JA, Sclambi CJ, Peterson BL, Richmond T, Thoreson M, Moran K, Dressmann HK, Jelinek J, Issa JP (2006) Phase I trial of sequential low-dose 5-aza-2′-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma. Clin Cancer Res 12:4619–4627
Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, Grever M, Galm O, Dauses T, Karp JE, Rudek MA, Zhao M, Smith BD, Manning J, Jiemjit A, Dover G, Mays A, Zwiebel J, Murgo A, Weng LJ, Herman JG (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66:6361–6369
Guo ZS, Hong JA, Irvine KR, Chen GA, Spiess PJ, Liu Y, Zeng G, Wunderlich JR, Nguyen DM, Restifo NP, Schrump DS (2006) De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 66:1105–1113
Hackanson B, Guo Y, Lübbert M (2005) The silence of the genes: epigenetic disturbances in haematopoietic malignancies. Expert Opin Ther Targets 9:45–61
Hambach L, Vermeij M, Buser A, Aghai Z, van der Kwast T, Goulmy E (2008) Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors. Blood 112:1844–1852
Hambach L, Ling KW, Pool J, Aghai Z, Blokland E, Tanke HJ, Bruijn JA, Halfwerk H, van Boven H, Wieles B, Goulmy E (2009) Hypomethylation drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy. Blood 113:2715–2722
Herranz M, Martin-Caballero J, Fraga MF, Ruiz-Cabello J, Flores JM, Desco M, Marquez VE, Esteller M (2006) The novel DNA methylation inhibitor zebularine is effective against the development of T-cell lymphoma. Blood 107:1174–1177
Hoshino K, Quintás-Cardama A, Yang H, Sanchez-Gonzalez B, Garcia-Manero G (2007) Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia. Leukemia 21:906–911
Hubeek I, Stam RW, Peters GJ, Broekhuizen R, Meijerink JP, van Wering ER, Gibson BE, Creutzig U, Zwaan CM, Cloos J, Kuik DJ, Pieters R, Kaspers GJ (2005) The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br J Cancer 93:1388–1394
Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, Talpaz M, Garcia-Manero G, Kantarjian HM (2005) Phase II study of low dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23:3948–3956
Jones LC, Tefferi A, Idos GE, Kumagai T, Hofmann WK, Koeffler HP (2004) RARbeta2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia. Oncogene 23:7846–7853
Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692
Kantarjian HM, O’Brien SM, Estey E, Giralt S, Beran M, Rios MB, Keating M, De Vos D, Talpaz M (1997a) Decitabine studies in chronic and acute myelogenous leukemia. Leukemia 11(1):35–36
Kantarjian HM, O’Brien SM, Keating M, Beran M, Estey E, Giralt S, Kornblau S, Rios MB, De Vos D, Talpaz M (1997b) Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 11:1617–1620
Kantarjian HM, O’Brien S, Cortes J, Giles FJ, Faderl S, Issa JP, Garcia-Manero G, Rios MB, Shan J, Andreeff M, Keating M, Talpaz M (2003) Results of decitabine (5-aza-2′-deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 98:522–528
Kantarjian HM, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C (2012a) Multicenter, randomized open-label phase III trial of decitabine versus patient choice, with physician advice of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30:2670–2677
Kantarjian HM, Roboz GJ, Rizzieri DA, Stock W, O’Connell CL, Griffiths EA (2012b) Results from the dose escalation phase of a randomized phase 1-2 first-in-human (FIH) study of SGI-110, a novel low volume stable subcutaneous (SQ) second generation hypomethylating agent (HMA) in patients with relapsed/refractory MDS and AML. Blood 120: ASH annual meeting abstract number 414
Knuth A, Jäger D, Jäger E (2000) Cancer immunotherapy in clinical oncology. Cancer Chemother Pharmacol 46:S46–S51
Koshy M, Dorn L, Bressler L, Molokie R, Lavelle D, Talischy N, Hoffman R, van Overveld W, DeSimone J (2000) 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 96:2379–2384
Kuang SQ, Tong WG, Yang H, Lin W, Lee MK, Fang ZH, Wei Y, Jelinek J, Issa JP, Garcia-Manero G (2008) Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphoblastic leukemia. Leukemia 8:1529–1538
Laliberté J, Marquez VE, Momparler RL (1992) Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2′-deoxycytidine by human cytidine deaminase. Cancer Chemother Pharmacol 30:7–11
Lavelle DE (2004) The molecular mechanism of fetal hemoglobin reactivation. Semin Hematol 41:3–10
Lavelle D, Chin J, Vaitkus K, Redkar S, Phiasivongsa P, Tang C, Will R, Hankewych M, Roxas B, Singh M, Saunthararajah Y, Desimone J (2007) Oral decitabine reactivates expression of the methylated gamma-globin gene in Papio anubis. Am J Hematol 82:981–985
Lemaire M, Momparler LF, Bernstein ML, Marquez VE, Momparler RL (2005) Enhancement of antineoplastic action of 5-aza-2′-deoxycytidine by zebularine on L1210 leukemia. Anticancer Drugs 16:301–308
Lemaire M, Momparler LF, Raynal NJM, Bernstein ML, Momparler RL (2009) Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2′-deoxycytidine. Cancer Chemother Pharmacol 63:411–416
Lübbert M (2000) DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol 249:135–164
Lübbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2001) Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 114:349–357
Lübbert M, Bertz H, Rüter B, Marks R, Claus R, Wäsch R, Finke J (2009) Non-intensive treatment with low-dose 5-aza-2′-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML-patients. Bone Marrow Transplant 44:585–588
Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Eckart Schaefer H, Ganser A, Aul C, de Witte T, Wijermans PW (2011) Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 29:1987–1996
Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, Kuendgen A, Rethwisch V, Ganser A, Platzbecker U, Galm O, Brugger W, Heil G, Hackanson B, Deschler B, Döhner K, Hagemeijer A, Wijermans PW, Döhner H (2012) A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica 97:393–401
Lübbert M, Bertz H, Müller MJ, Finke J (2013) When azanucleoside treatment can be curative: nonintensive bridging strategy before allografting in older patients with myelodysplastic syndrome/acute myeloid leukemia. J Clin Oncol 31:822–823
Marquez VE, Kelley JA, Agbaria R, Ben-Kasus T, Cheng JC, Yoo CB, Jones PA (2005) Zebularine: a unique molecule for an epigenetically based strategy in cancer chemotherapy. Ann NY Acad Sci 1058:246–254
Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I, Warrell R, Nimer S (2006) Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 2:212–217
Momparler RL, Derse D (1979) Kinetics of phosphorylation of 5-aza-2′-deoxycytidine by deoxycytidine kinase. Biochem Pharmacol 28:1443–1444
Momparler RL, Bouchard J, Samson J (1985a) Induction of differentiation and inhibition of DNA methylation in HL-60 myeloid leukemic cells by 5-aza-2′-deoxycytidine. Leuk Res 9:1361–1366
Momparler RL, Rivard GE, Gyger M (1985b) Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther 30:277–286
Momparler RL, Bouffard DY, Momparler LF, Dionne J, Belanger K, Ayoub J (1997) Pilot phase-I-II study on 5-aza-2′-deoxycytidine (decitabine) in patients with metastatic lung cancer. Anticancer Drugs 8:358–368
Montero AJ, Diaz-Montero CM, Mao L, Youssef EM, Estecio M, Shen L, Issa JP (2006) Epigenetic inactivation of EGFR by CpG island hypermethylation in cancer. Cancer Biol Ther 5:1494–1501
Mund C, Brueckner B, Lyko F (2006) Reactivation of epigenetically silenced genes by DNA methyltransferase inhibitors: basic concepts and clinical applications. Epigenetics 1:7–13
Odenike OM, Godwin JE, van Besien K, Huo D, Stiff PJ, Sher D, Klekowski N, Green M, Larson RA, Stock W (2006) Phase II study of decitabine in myelofibrosis with myeloid metaplasia. Blood 108: 317b (abstract 4923)
Oi S, Natsume A, Ito M, Kondo Y, Shimato S, Maeda Y, Saito K, Wakabayashi T (2009) Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2′-deoxycytidine in glioma cells. J Neurooncol 92:15–22
Oki Y, Kantarjian H, Gharibyan V, Jones D, O’brien S, Verstovsek S, Cortes J, Morris GM, Garcia-Manero G, Issa JP (2007) Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer 109:899–906
Petti MC, Mandelli F, Zagonel V, De Gregoris C, Merola MC, Latagliata R, Gattei V, Fazi P, Monfardini S, Pino A (1993) Pilot study of 5-aza-2′-deoxycytidine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia 7:36–41
Pinto A, Attadia V, Fusco A, Ferrara F, Spada OA, Di Fiore PP (1984) 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood 64:922–929
Pinto A, Zagonel V, Attadia V, Bullian PL, Gattei V, Carbone A, Monfardini S, Colombatti A (1989) 5-Aza-2′-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant 4(Suppl 3):28–32
Pliml J, Sorm F (1964) Synthesis of 2′-deoxy-D-ribofuranosyl-5-azacytosine. Coll Czeck Chem Commun 29:2576–2577
Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R (2000) Reversal of drug resistance in human tumor xenografts by 2′deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 60:6039–6044
Pohlmann P, DiLeone LP, Cancella AI, Caldas AP, Dal Lago L, Campos O Jr, Monega E, Rivoire W, Schwartsmann G (2002) Phase II trial of cisplatin plus decitabine, a new hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix. Am J Clin Oncol 25:496–501
Ravandi F, Kantarjian H, Cohen A, Davis M, O’Brien S, Anderlini P, Andersson B, Claxton D, Donato M, Gajewski J, Khouri I, Korbling M, Ueno N, de Vos D, Champlin R, Giralt S (2001) Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study. Bone Marrow Transplant 27:1221–1225
Richel DJ, Colly LP, Kluin-Nelemans JC, Willemze R (1991) The antileukemic activity of 5-aza-2′-deoxycytidine (Aza-dC) in patients with relapsed and resistant leukemia. Br J Cancer 64:144–148
Rivard GE, Momparler RL, Demers J, Benoit P, Raymond R, Lin K, Momparler LF (1981) Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res 5:453–462
Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A (2004) Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood 10:2492–2498
Roman-Gomez J, Cordeu L, Agirre X, Jimenez-Velasco A, San Jose-Eneriz E, Garate L, Calasanz MJ, Heiniger A, Torres A, Prosper F (2007) Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia. Blood 8:3462–3469
Rüter B, Wijermans PW, Lübbert M (2006) Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2′-deoxycytidine retreatment in high-risk myelodysplasia patients. Cancer 106:1744–1750
Sacchi S, Talpaz M, O’Brien S, Cortes J, Kantarjian HM (1998) Decitabine, a hypomethylating agent, is active for the treatment of chronic myelogenous leukemia (CML) in non-lymphoid blastic phase (BP). Blood 92 (Suppl 1): 252a (abstract)
Sacchi S, Kantarjian HM, O’Brien S, Cortes J, Rios MB, Giles FJ, Beran M, Koller CA, Keating MJ, Talpaz M (1999) Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 86:2632–2641
Samlowski WE, Leachman SA, Wade M, Cassidy P, Porter-Gill P, Busby L, Wheeler R, Boucher K, Fitzpatrick F, Jones DA, Karpf AR (2005) Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation. J Clin Oncol 23:3897–3905
Santi DV, Garret CD, Barr PJ (1983) On the mechanism of inhibition of DNA-cytosine methyltransferase by cytidine analogs. Cell 83:83–89
Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J (2003) Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 102:3865–3870
Saunthararajah Y (2007) Decitabine and sickle cell disease: molecular therapy for a molecular disease. Pediatr Hematol Oncol 24:465–468
Saunthararajah Y, Molokie R, Saraf S, Sidhwani S, Gowhari M, Vara S, Lavelle D, DeSimone J (2008) Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol 141:126–129
Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, Hancox A, Hong JA, Chen GA, Pishchik V, Figg WD, Murgo AJ, Steinberg SM (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
Schwartsmann G, Fernandes MS, Schaan MD, Moschen M, Gerhardt LM, DiLeone L, Loitzembauer B, Kalakun L (1997) Decitabine (5-aza-2′-deoxycytidine; decitabine) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11(Suppl 1):28–31
Schwartsmann G, Schunemann H, Gorini CN, Filho AF, Garbino C, Sabini G, Muse I, DiLeone L, Mans DR (2000) A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer. Invest New Drugs 18:83–91
Scott SA, Lakshimikuttysamma A, Sheridan DP, Sanche SE, Geyer CR, DeCoteau JF (2007) Zebularine inhibits human acute myeloid leukemia cell growth vitro in association with p15INK4B demethylation and reexpression. Exp Hematol 35:263–273
Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S, Imai K, Kantarjian HM, Issa JP, Garcia-Manero G (2003) Aberrant DNA methylation of p57KIP2 identifies a cell cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 101:4131–4136
Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, Berry D, Ahmed S, Zhu W, Pierce S, Kondo Y, Oki Y, Jelinek J, Saba H, Estey E, Issa JP (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:605–613
Shi J, Zhao Y, Ishii T, Hu W, Sozer S, Zhang W, Bruno E, Lindgren V, Xu M, Hoffman R (2007) Effects of chromatin-modifying agents on CD34+ cells from patients with idiopathic myelofibrosis. Cancer Res 67:6417–6424
Sigalotti L, Coral S, Nardi G, Spessotto A, Cortini E, Cattarossi I, Colizzi F, Altomonte M, Maio M (2002) Promoter methylation controls the expression fo MAGE2, 3 and 4 genes in human cutaneous melanoma. J Immunother 25:16–26
Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R, Colizzi F, Fonsatti E, Traversari C, Altomonte M, Maio M (2004) Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2′-deoxycytidine. Cancer Res 64:9167–9171
Sigalotti L, Coral S, Fratta E, Lamaj E, Danielli R, Di Giacomo AM, Altomonte M, Maio M (2005) Epigenetic modulation of solid tumors as a novel approach for cancer immunotherapy. Semin Oncol 32:473–478
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
Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner LA, McGill S, Wang L, Zhang WJ, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17:1582–1590
Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123:8–13
Thibault A, Figg WD, Bergan RC, Lush RM, Myers CE, Tompkins A, Reed E, Samid D (1998) A phase-II study of 5-aza-2′-deoxycytidine (decitabine) in hormone-independent metastatic (D2) prostate cancer. Tumori 84:87–89
Trompeter S, Roberts I (2009) Haemoglobin F modulation in childhood sickle cell disease. Brit J Haematol 144:308–316
van den Bosch J, Lübbert M, Verhoef G, Wijermans PW (2004) The effects of 5-aza-2′-deoxycytidine (decitabine) on the platelet count in patients with intermediate and high-risk myelodysplastic syndrome. Leuk Res 28:785–790
Venturelli S, Armeanu S, Pathil A, Hsieh CJ, Weiss TS, Vonthein R, Wehrmann M, Gregor M, Lauer UM, Bitzer M (2007) Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma. Cancer 109:2132–2141
Vermorken JB, Tumolo S, Roozendaal KJ, Guastalla JP, Splinter Ted AW, Renard J (1991) 5-Aza-2′-deoxycytidine in advanced or recurrent cancer of the uterine cervix. Eur J Cancer 27:216–217
Wang JC, Chen W, Nallusamy S, Chen C, Novetsky AD (2002) Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation. Brit J Haematol 116:582–586
Wang WC (2008) The pharmacotherapy of sickle cell disease. Expert Opin Pharmacother 9:3069–3082
Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, Lassam N, Treisman J, Rosenberg SA (1994) Expression of the MAGE-I tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res 54:1766–1771
Wijermans PW, Krulder JW, Huijgens PC, Neve P (1997) Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 11:19–23
Wijermans PW, Lübbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2000) Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18:956–962
Wijermans PW, Lübbert M, Verhoef G, Klimek V, Bosly A (2005) An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2′-deoxycytidine (decitabine) in 177 patients. Ann Hematol 84(Suppl 1):9–17
Willemze R, Archimbaud E, Muus P (1993) Preliminary results with 5-aza-2′deoxycytidine (DAC)-containing chemotherapy in patients with relapsed or refractory acute leukemia. The EORTC Leukemia Cooperative Group. Leukemia 7(Suppl 1):49–50
Willemze R, Suciu S, Archimbaud E, Muus P, Stryckmans P, Louwagie EA, Berneman Z, Tjean M, Wijermans P, Döhner H, Jehn U, Labar B, Jaksic B, Dardenne M, Zittoun R (1997) A randomized phase-II study on the effects of 5-aza-2′-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase-II study. Leukemia 11(Suppl 1):24–27
Wilson VL, Jones PA, Momparler RL (1983) Inhibition of DNA methylation in L1210 leukemia cells by 5-aza-2′-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res 43:3493–3496
Yanez L, Bermudez A, Richard C, Bureo E, Iriondo A (2009) Letter to the editor: Successful induction therapy with decitabine in refractory childhood acute lymphoblastic leukemia. Leukemia 23:1342–1343
Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, Luna R, Rashid A, Shen L, Estecio MR, Kantarjian HM, Garcia-Manero G, Issa JP (2006) DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia. Cancer Res 66:5495–5503
Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G (2005) Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk Res 29:739–748
Yang H, Kadia T, Xiao L, Bueso-Ramos CE, Hoshino K, Thomas DA, O’Brien S, Jabbour E, Pierce S, Rosner GL, Kantarjian HM, Garcia-Manero G (2009) Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia. Blood 113:1892–1898
Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50
Zagonel V, Pinto A, Bullian PL, Sorio R, Gattei V, Curri G, De Rosa L, Attadia V, Monfardini S (1990) 5-Aza-2′-deoxycytidine as a differentiation inducer in human hemopoietic malignancies: preliminary clinical report. In: Momparler RL, de Vos D (eds) PCH 5-Aza-2′-deoxycytidine: preclinical and clinical studies. Haarlem, Netherlands, pp 165–181
Zagonel V, Lo Re G, Marotta G, Barbare R, Sardeo R, Gattei V, de Angelis V, Montardinni S, Pinto A (1993) 5-Aza-2′-deoxycytidine (decitabine) induces trilineage response in unfavourable myelodysplastic syndrome. Leukemia 7(Suppl 1):30–35
Zhou L, Cheng X, Connolly BA, Dickman MJ, Hurd PJ, Hornby DP (2002) Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J Mol Biol 23:591–599
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Hackanson, B., Daskalakis, M. (2014). Decitabine. 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_18
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