Promises and challenges of anticancer drugs that target the epigenome

• Berger SL , KouzaridesT, ShiekhattarR, ShilatifardA. An operational definition of epigenetics. Genes Dev.23(7) , 781–783 (2009).
   PubMed Web of Science ®Google Scholar
• Rodriguez-Paredes M , EstellerM. Cancer epigenetics reaches mainstream oncology. Nat. Med.17(3) , 330–339 (2011).
   PubMed Web of Science ®Google Scholar
• Jones PA , BaylinSB. The epigenomics of cancer. Cell128(4) , 683–692 (2007).
   PubMed Web of Science ®Google Scholar
• Esteller M . Epigenetics in cancer. N. Engl. J. Med.358(11) , 1148–1159 (2008).
   PubMed Web of Science ®Google Scholar
• Luger K , MaderAW, RichmondRK, SargentDF, RichmondTJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature389(6648) , 251–260 (1997).
   PubMed Web of Science ®Google Scholar
• Jenuwein T , AllisCD. Translating the histone code. Science293(5532) , 1074–1080 (2001).
   PubMed Web of Science ®Google Scholar
• Guil S , EstellerM. DNA methylomes, histone codes and miRNAs: tying it all together. Int. J. Biochem. Cell Biol.41(1) , 87–95 (2009).
   PubMed Web of Science ®Google Scholar
• Bird A . DNA methylation patterns and epigenetic memory. Genes Dev.16(1) , 6–21 (2002).
   PubMed Web of Science ®Google Scholar
• Pradhan S , TalbotD, ShaMet al. Baculovirus-mediated expression and characterization of the full-length murine DNA methyltransferase. Nucleic Acids Res. 25(22) , 4666–4673 (1997).
   PubMed Web of Science ®Google Scholar
• Okano M , BellDW, HaberDA, LiE. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99(3) , 247–257 (1999).
   PubMed Web of Science ®Google Scholar
• Goll MG , BestorTH. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem.74 , 481–514 (2005).
   PubMed Web of Science ®Google Scholar
• Ramsahoye BH , BiniszkiewiczD, LykoF, ClarkV, BirdAP, JaenischR. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc. Natl Acad. Sci. USA97(10) , 5237–5242 (2000).
   PubMed Web of Science ®Google Scholar
• Lister R , PelizzolaM, DowenRHet al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271) , 315–322 (2009).
   PubMed Web of Science ®Google Scholar
• Bernstein BE , MeissnerA, LanderES. The mammalian epigenome. Cell128(4) , 669–681 (2007).
   PubMed Web of Science ®Google Scholar
• Tahiliani M , KohKP, ShenYet al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929) , 930–935 (2009).
   PubMed Web of Science ®Google Scholar
• Ito S , D‘AlessioAC, TaranovaOV, HongK, SowersLC, ZhangY. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature466(7310) , 1129–1133 (2010).
   PubMed Web of Science ®Google Scholar
• Koh KP , YabuuchiA, RaoSet al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8(2) , 200–213 (2011).
   PubMed Web of Science ®Google Scholar
• Ito S , ShenL, DaiQet al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047) , 1300–1303 (2011).
   PubMed Web of Science ®Google Scholar
• Zhang H , ZhangX, ClarkE, MulcaheyM, HuangS, ShiYG. TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res.20(12) , 1390–1393 (2010).
   PubMed Web of Science ®Google Scholar
• Wu SC , ZhangY. Active DNA demethylation: many roads lead to Rome. Nat. Rev. Mol. Cell Biol.11(9) , 607–620 (2010).
   PubMed Web of Science ®Google Scholar
• Mohr F , DohnerK, BuskeC, RawatVP. TET genes: new players in DNA demethylation and important determinants for stemness. Exp. Hematol.39(3) , 272–281 (2011).
   PubMed Web of Science ®Google Scholar
• Ficz G , BrancoMR, SeisenbergerSet al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473(7347) , 398–402 (2011).
   PubMed Web of Science ®Google Scholar
• Pastor WA , PapeUJ, HuangYet al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473(7347) , 394–397 (2011).
   PubMed Web of Science ®Google Scholar
• Williams K , ChristensenJ, PedersenMTet al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473(7347) , 343–348 (2011).
   PubMed Web of Science ®Google Scholar
• Wu H , D‘AlessioAC, ItoSet al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473(7347) , 389–393 (2011).
   PubMed Web of Science ®Google Scholar
• Bhutani N , BradyJJ, DamianM, SaccoA, CorbelSY, BlauHM. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature463(7284) , 1042–1047 (2010).
   PubMed Web of Science ®Google Scholar
• Nightingale KP , O‘NeillLP, TurnerBM. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev.16(2) , 125–136 (2006).
   PubMed Web of Science ®Google Scholar
• Sawan C , HercegZ. Histone modifications and cancer. Adv. Genet.70 , 57–85 (2010).
   PubMed Web of Science ®Google Scholar
• Portela A , EstellerM. Epigenetic modifications and human disease. Nat. Biotechnol.28(10) , 1057–1068 (2010).
   PubMed Web of Science ®Google Scholar
• Shahbazian MD , GrunsteinM. Functions of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem.76 , 75–100 (2007).
   PubMed Web of Science ®Google Scholar
• Grunstein M . Histone acetylation in chromatin structure and transcription. Nature389(6649) , 349–352 (1997).
   PubMed Web of Science ®Google Scholar
• Clayton AL , HazzalinCA, MahadevanLC. Enhanced histone acetylation and transcription: a dynamic perspective. Mol. Cell23(3) , 289–296 (2006).
   PubMed Web of Science ®Google Scholar
• Li B , CareyM, WorkmanJL. The role of chromatin during transcription. Cell128(4) , 707–719 (2007).
   PubMed Web of Science ®Google Scholar
• Lee KK , WorkmanJL. Histone acetyltransferase complexes: one size doesn‘t fit all. Nat. Rev. Mol. Cell Biol.8(4) , 284–295 (2007).
   PubMed Web of Science ®Google Scholar
• Choudhary C , KumarC, GnadFet al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942) , 834–840 (2009).
   PubMed Web of Science ®Google Scholar
• Glozak MA , SenguptaN, ZhangX, SetoE. Acetylation and deacetylation of non-histone proteins. Gene363 , 15–23 (2005).
   PubMed Web of Science ®Google Scholar
• Neugebauer RC , SipplW, JungM. Inhibitors of NAD+ dependent histone deacetylases (sirtuins). Curr. Pharm. Des.14(6) , 562–573 (2008).
   PubMed Web of Science ®Google Scholar
• Yang XJ , SetoE. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol.9(3) , 206–218 (2008).
   PubMed Web of Science ®Google Scholar
• Buchwald M , KramerOH, HeinzelT. HDACi – targets beyond chromatin. Cancer Lett.280(2) , 160–167 (2009).
   PubMed Web of Science ®Google Scholar
• Shi Y , LanF, MatsonCet al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119(7) , 941–953 (2004).
   PubMed Web of Science ®Google Scholar
• Klose RJ , KallinEM, ZhangY. JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet.7(9) , 715–727 (2006).
   PubMed Web of Science ®Google Scholar
• Spannhoff A , SipplW, JungM. Cancer treatment of the future: inhibitors of histone methyltransferases. Int. J. Biochem. Cell Biol.41(1) , 4–11 (2009).
   PubMed Web of Science ®Google Scholar
• Zhang Y , ReinbergD. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev.15(18) , 2343–2360 (2001).
   PubMed Web of Science ®Google Scholar
• Margueron R , TrojerP, ReinbergD. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev.15(2) , 163–176 (2005).
   PubMed Web of Science ®Google Scholar
• Wiencke JK , ZhengS, MorrisonZ, YehRF. Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells. Oncogene27(17) , 2412–2421 (2008).
   PubMed Web of Science ®Google Scholar
• Bernstein BE , MikkelsenTS, XieXet al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2) , 315–326 (2006).
   PubMed Web of Science ®Google Scholar
• Cloos PA , ChristensenJ, AggerK, HelinK. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev.22(9) , 1115–1140 (2008).
   PubMed Web of Science ®Google Scholar
• Fazi F , RacanicchiS, ZardoGet al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12(5) , 457–466 (2007).
   PubMed Web of Science ®Google Scholar
• Nelson KM , WeissGJ. MicroRNAs and cancer: past, present, and potential future. Mol. Cancer Ther.7(12) , 3655–3660 (2008).
   PubMed Web of Science ®Google Scholar
• Feinberg AP , OhlssonR, HenikoffS. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet.7(1) , 21–33 (2006).
   PubMed Web of Science ®Google Scholar
• Feinberg AP , VogelsteinB. Alterations in DNA methylation in human colon neoplasia. Semin. Surg. Oncol.3(3) , 149–151 (1987).
   PubMedGoogle Scholar
• Cadieux B , ChingTT, VandenbergSR, CostelloJF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res.66(17) , 8469–8476 (2006).
   PubMed Web of Science ®Google Scholar
• Feinberg AP , TyckoB. The history of cancer epigenetics. Nat. Rev. Cancer4(2) , 143–153 (2004).
   PubMed Web of Science ®Google Scholar
• Ogino S , NoshoK, KirknerGJet al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J. Natl Cancer Inst. 100(23) , 1734–1738 (2008).
   PubMedGoogle Scholar
• Jones PA , LairdPW. Cancer epigenetics comes of age. Nat. Genet.21(2) , 163–167 (1999).
   PubMed Web of Science ®Google Scholar
• Humeniuk R , MishraPJ, BertinoJR, BanerjeeD. Molecular targets for epigenetic therapy of cancer. Curr. Pharm. Biotechnol.10(2) , 161–165 (2009).
   PubMed Web of Science ®Google Scholar
• Belinsky SA , NikulaKJ, PalmisanoWAet al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Natl Acad. Sci. USA 95(20) , 11891–11896 (1998).
   PubMed Web of Science ®Google Scholar
• Herranz M , EstellerM. DNA methylation and histone modifications in patients with cancer: potential prognostic and therapeutic targets. Methods Mol. Biol.361 , 25–62 (2007).
   PubMedGoogle Scholar
• Feinberg AP , CuiH, OhlssonR. DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. Semin. Cancer Biol.12(5) , 389–398 (2002).
   PubMed Web of Science ®Google Scholar
• Wilson AS , PowerBE, MolloyPL. DNA hypomethylation and human diseases. Biochim. Biophys. Acta1775(1) , 138–162 (2007).
   PubMed Web of Science ®Google Scholar
• Ogawa O , EcclesMR, SzetoJet al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms‘ tumour. Nature 362(6422) , 749–751 (1993).
   PubMed Web of Science ®Google Scholar
• Watt PM , KumarR, KeesUR. Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia. Genes Chromosomes Cancer29(4) , 371–377 (2000).
   PubMed Web of Science ®Google Scholar
• Samuel MS , SuzukiH, BuchertMet al. Elevated Dnmt3a activity promotes polyposis in Apc(Min) mice by relaxing extracellular restraints on Wnt signaling. Gastroenterology 137(3) , 902–913, 913.e1–11 (2009).
   PubMed Web of Science ®Google Scholar
• Eads CA , NickelAE, LairdPW. Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer Res.62(5) , 1296–1299 (2002).
   PubMed Web of Science ®Google Scholar
• Linhart HG , LinH, YamadaYet al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 21(23) , 3110–3122 (2007).
   PubMed Web of Science ®Google Scholar
• Sansom OJ , BergerJ, BishopSM, HendrichB, BirdA, ClarkeAR. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat. Genet.34(2) , 145–147 (2003).
   PubMed Web of Science ®Google Scholar
• Wang L , WangJ, SunSet al. A novel DNMT3B subfamily, δDNMT3B, is the predominant form of DNMT3B in non-small cell lung cancer. Int. J. Oncol. 29(1) , 201–207 (2006).
   PubMed Web of Science ®Google Scholar
• Ostler KR , DavisEM, PayneSLet al. Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26(38) , 5553–5563 (2007).
   PubMed Web of Science ®Google Scholar
• Nakagawa T , KanaiY, SaitoY, KitamuraT, KakizoeT, HirohashiS. Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. J. Urol.170(6 Pt 1) , 2463–2466 (2003).
   PubMed Web of Science ®Google Scholar
• Nosho K , ShimaK, IraharaNet al.DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin. Cancer Res.15(11) , 3663–3671 (2009).
   PubMed Web of Science ®Google Scholar
• Gopalakrishnan S , Van Emburgh BO, Shan J et al. A novel DNMT3B splice variant expressed in tumor and pluripotent cells modulates genomic DNA methylation patterns and displays altered DNA binding. Mol. Cancer Res.7(10) , 1622–1634 (2009).
   PubMed Web of Science ®Google Scholar
• Walter MJ , DingL, ShenDet al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25(7) , 1153–1158 (2011).
   PubMed Web of Science ®Google Scholar
• Yan XJ , XuJ, GuZHet al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43(4) , 309–315 (2011).
   PubMed Web of Science ®Google Scholar
• Ley TJ , DingL, WalterMJet al.DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med.363(25) , 2424–2433 (2010).
   PubMed Web of Science ®Google Scholar
• Kanai Y , UshijimaS, NakanishiY, SakamotoM, HirohashiS. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett.192(1) , 75–82 (2003).
   PubMed Web of Science ®Google Scholar
• Langemeijer SM , KuiperRP, BerendsMet al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41(7) , 838–842 (2009).
   PubMed Web of Science ®Google Scholar
• Langemeijer SM , JansenJH, HooijerJet al.TET2 mutations in childhood leukemia. Leukemia25(1) , 189–192 (2011).
   PubMed Web of Science ®Google Scholar
• Ko M , HuangY, JankowskaAMet al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468(7325) , 839–843 (2010).
   PubMed Web of Science ®Google Scholar
• Moran-Crusio K , ReavieL, ShihAet al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20(1) , 11–24 (2011).
   PubMed Web of Science ®Google Scholar
• Quivoron C , CouronneL, Della Valle V et al. TET2 Inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell20(1) , 25–38 (2011).
   PubMed Web of Science ®Google Scholar
• Figueroa ME , Abdel-WahabO, LuCet al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6) , 553–567 (2010).
   PubMed Web of Science ®Google Scholar
• Prensner JR , ChinnaiyanAM. Metabolism unhinged: IDH mutations in cancer. Nat. Med.17(3) , 291–293 (2011).
   PubMed Web of Science ®Google Scholar
• Fraga MF , BallestarE, Villar-GareaAet al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37(4) , 391–400 (2005).
   PubMed Web of Science ®Google Scholar
• Bots M , JohnstoneRW. Rational combinations using HDAC inhibitors. Clin. Cancer Res.15(12) , 3970–3977 (2009).
   PubMed Web of Science ®Google Scholar
• Bereshchenko OR , GuW, Dalla-FaveraR. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet.32(4) , 606–613 (2002).
   PubMed Web of Science ®Google Scholar
• Mullighan CG , ZhangJ, KasperLHet al.CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature471(7337) , 235–239 (2011).
   PubMed Web of Science ®Google Scholar
• Pasqualucci L , Dominguez-SolaD, ChiarenzaAet al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471(7337) , 189–195 (2011).
   PubMed Web of Science ®Google Scholar
• Ropero S , FragaMF, BallestarEet al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat. Genet. 38(5) , 566–569 (2006).
   PubMed Web of Science ®Google Scholar
• Vaziri H , DessainSK, Ng Eaton E et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell107(2) , 149–159 (2001).
   PubMed Web of Science ®Google Scholar
• Firestein R , BlanderG, MichanSet al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3(4) , e2020 (2008).
   PubMed Web of Science ®Google Scholar
• Herranz D , SerranoM. SIRT1: recent lessons from mouse models. Nat. Rev. Cancer10(12) , 819–823 (2010).
   PubMed Web of Science ®Google Scholar
• Ellis L , AtadjaPW, JohnstoneRW. Epigenetics in cancer: targeting chromatin modifications. Mol. Cancer Ther.8(6) , 1409–1420 (2009).
   PubMed Web of Science ®Google Scholar
• Deng Q , LiY, TedescoD, LiaoR, FuhrmannG, SunP. The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins. Cancer Res.65(18) , 8298–8307 (2005).
   PubMed Web of Science ®Google Scholar
• Chan EM , ChanRJ, ComerEMet al. MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Exp. Hematol. 35(12) , 1782–1792 (2007).
   PubMed Web of Science ®Google Scholar
• Panagopoulos I , FioretosT, IsakssonMet al. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum. Mol. Genet. 10(4) , 395–404 (2001).
   PubMed Web of Science ®Google Scholar
• Yang XJ . The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res.32(3) , 959–976 (2004).
   PubMed Web of Science ®Google Scholar
• Gayther SA , BatleySJ, LingerLet al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24(3) , 300–303 (2000).
   PubMed Web of Science ®Google Scholar
• Kazantsev AG , ThompsonLM. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat. Rev. Drug. Discov.7(10) , 854–868 (2008).
   PubMed Web of Science ®Google Scholar
• Gorrini C , SquatritoM, LuiseCet al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448(7157) , 1063–1067 (2007).
   PubMed Web of Science ®Google Scholar
• Cao R , WangL, WangHet al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298(5595) , 1039–1043 (2002).
   PubMed Web of Science ®Google Scholar
• Kleer CG , CaoQ, VaramballySet al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100(20) , 11606–11611 (2003).
   PubMed Web of Science ®Google Scholar
• Kondo Y , ShenL, ChengASet al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat. Genet. 40(6) , 741–750 (2008).
   PubMed Web of Science ®Google Scholar
• Morin RD , JohnsonNA, SeversonTMet al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42(2) , 181–185 (2010).
   PubMed Web of Science ®Google Scholar
• Sneeringer CJ , ScottMP, KuntzKWet al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107(49) , 20980–20985 (2010).
   PubMed Web of Science ®Google Scholar
• Yap DB , ChuJ, BergTet al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117(8) , 2451–2459 (2011).
   PubMed Web of Science ®Google Scholar
• van Haaften G , DalglieshGL, DaviesHet al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41(5) , 521–523 (2009).
   PubMed Web of Science ®Google Scholar
• Dalgliesh GL , FurgeK, GreenmanCet al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463(7279) , 360–363 (2010).
   PubMed Web of Science ®Google Scholar
• Ernst T , ChaseAJ, ScoreJet al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42(8) , 722–726 (2010).
   PubMed Web of Science ®Google Scholar
• Ceol CJ , HouvrasY, Jane-ValbuenaJet al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471(7339) , 513–517 (2011).
   PubMed Web of Science ®Google Scholar
• Kim YR , LeeBK, ParkRYet al. Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 10 , 197 (2010).
   PubMed Web of Science ®Google Scholar
• Northcott PA , NakaharaY, WuXet al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat. Genet. 41(4) , 465–472 (2009).
   PubMed Web of Science ®Google Scholar
• Kawazu M , SasoK, TongKIet al. Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development. PLoS ONE 6(3) , e17830 (2011).
   PubMed Web of Science ®Google Scholar
• Hess JL . MLL: a histone methyltransferase disrupted in leukemia. Trends Mol. Med.10(10) , 500–507 (2004).
   PubMed Web of Science ®Google Scholar
• Slany RK . The molecular biology of mixed lineage leukemia. Haematologica94(7) , 984–993 (2009).
   PubMed Web of Science ®Google Scholar
• Nguyen AT , TaranovaO, HeJ, ZhangY. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood117(25) , 6912–6922 (2011).
   PubMed Web of Science ®Google Scholar
• Mohan M , LinC, GuestE, ShilatifardA. Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. Nat. Rev. Cancer10(10) , 721–728 (2010).
   PubMed Web of Science ®Google Scholar
• Ghoshal K , DattaJ, MajumderSet al. 5-aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell Biol. 25(11) , 4727–4741 (2005).
   PubMed Web of Science ®Google Scholar
• Kuo HK , GriffithJD, KreuzerKN. 5-azacytidine induced methyltransferase-DNA adducts block DNA replication in vivo. Cancer Res.67(17) , 8248–8254 (2007).
   PubMed Web of Science ®Google Scholar
• Issa JP , KantarjianHM. Targeting DNA methylation. Clin. Cancer Res.15(12) , 3938–3946 (2009).
   PubMed Web of Science ®Google Scholar
• Vigil CE , Martin-SantosT, Garcia-ManeroG. Safety and efficacy of azacitidine in myelodysplastic syndromes. Drug Des. Devel. Ther.4 , 221–229 (2010).
   PubMed Web of Science ®Google Scholar
• Garcia JS , JainN, GodleyLA. An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes. Onco. Targets Ther.3 , 1–13 (2010).
   PubMed Web of Science ®Google Scholar
• Graham JS , KayeSB, BrownR. The promises and pitfalls of epigenetic therapies in solid tumours. Eur. J. Cancer45(7) , 1129–1136 (2009).
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G , GoreSD, CogleCet al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J. Clin. Oncol. 29(18) , 2521–2527 (2011).
   PubMed Web of Science ®Google Scholar
• Herranz M , Martin-CaballeroJ, FragaMFet al. The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. Blood 107(3) , 1174–1177 (2006).
   PubMed Web of Science ®Google Scholar
• Holleran JL , PariseRA, JosephEet al. Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the DNA methyltransferase inhibitor, zebularine. Clin. Cancer Res. 11(10) , 3862–3868 (2005).
   PubMed Web of Science ®Google Scholar
• Chuang JC , WarnerSL, VollmerDet al. S110, a 5-aza-2´-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther. 9(5) , 1443–1450 (2010).
   PubMed Web of Science ®Google Scholar
• Rhee I , BachmanKE, ParkBHet al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416(6880) , 552–556 (2002).
   PubMed Web of Science ®Google Scholar
• Robert MF , MorinS, BeaulieuNet al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat. Genet. 33(1) , 61–65 (2003).
   PubMed Web of Science ®Google Scholar
• Plummer R , VidalL, GriffinMet al. Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin. Cancer Res. 15(9) , 3177–3183 (2009).
   PubMed Web of Science ®Google Scholar
• Klisovic RB , StockW, CatalandSet al. A Phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia. Clin. Cancer Res. 14(8) , 2444–2449 (2008).
   PubMed Web of Science ®Google Scholar
• Wagner JM , HackansonB, LubbertM, JungM. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin. Epigenetics1(3–4) , 117–136 (2010).
   PubMed Web of Science ®Google Scholar
• Keppler BR , ArcherTK. Chromatin-modifying enzymes as therapeutic targets – Part 1. Expert Opin. Ther. Targets12(10) , 1301–1312 (2008).
   PubMed Web of Science ®Google Scholar
• Bantscheff M , HopfC, SavitskiMMet al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29(3) , 255–265 (2011).
   PubMed Web of Science ®Google Scholar
• Olsen EA , KimYH, KuzelTMet al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25(21) , 3109–3115 (2007).
   PubMed Web of Science ®Google Scholar
• Duvic M , TalpurR, NiXet al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109(1) , 31–39 (2007).
   PubMed Web of Science ®Google Scholar
• Piekarz RL , FryeR, TurnerMet al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J. Clin. Oncol. 27(32) , 5410–5417 (2009).
   PubMed Web of Science ®Google Scholar
• Whittaker SJ , DemierreMF, KimEJet al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 28(29) , 4485–4491 (2010).
   PubMed Web of Science ®Google Scholar
• Ellis L , PanY, SmythGKet al. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin. Cancer Res. 14(14) , 4500–4510 (2008).
   PubMed Web of Science ®Google Scholar
• Piekarz RL , FryeR, PrinceHMet al. Phase II trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117(22) , 5827–5834 (2011).
   PubMed Web of Science ®Google Scholar
• Dickinson M , RitchieD, DeangeloDJet al. Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin lymphoma. Br. J. Haematol. 147(1) , 97–101 (2009).
   PubMed Web of Science ®Google Scholar
• Steele NL , PlumbJA, VidalLet al. A Phase I pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin. Cancer Res. 14(3) , 804–810 (2008).
   PubMed Web of Science ®Google Scholar
• Siegel D , HusseinM, BelaniCet al. Vorinostat in solid and hematologic malignancies. J. Hematol. Oncol. 2 , 31 (2009).
   PubMed Web of Science ®Google Scholar
• Hauschild A , TrefzerU, GarbeCet al. Multicenter Phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. Melanoma Res. 18(4) , 274–278 (2008).
   PubMed Web of Science ®Google Scholar
• Schrump DS , FischetteMR, NguyenDMet al. Clinical and molecular responses in lung cancer patients receiving romidepsin. Clin. Cancer Res. 14(1) , 188–198 (2008).
   PubMed Web of Science ®Google Scholar
• Bradley D , RathkopfD, DunnRet al. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase II Consortium. Cancer 115(23) , 5541–5549 (2009).
   PubMed Web of Science ®Google Scholar
• Traynor AM , DubeyS, EickhoffJCet al. Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network Phase II study. J. Thorac. Oncol. 4(4) , 522–526 (2009).
   PubMed Web of Science ®Google Scholar
• Lane AA , ChabnerBA. Histone deacetylase inhibitors in cancer therapy. J. Clin. Oncol.27(32) , 5459–5468 (2009).
   PubMed Web of Science ®Google Scholar
• Copeland RA , SolomonME, RichonVM. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov.8(9) , 724–732 (2009).
   PubMed Web of Science ®Google Scholar
• Hamada S , SuzukiT, MinoKet al. Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. J. Med. Chem. 53(15) , 5629–5638 (2010).
   PubMed Web of Science ®Google Scholar
• Heltweg B , GatbontonT, SchulerADet al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66(8) , 4368–4377 (2006).
   PubMed Web of Science ®Google Scholar
• Isham CR , TibodeauJD, JinW, XuR, TimmMM, BibleKC. Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. Blood109(6) , 2579–2588 (2007).
   PubMed Web of Science ®Google Scholar
• Lakshmikuttyamma A , ScottSA, DecoteauJF, GeyerCR. Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition. Oncogene29(4) , 576–588 (2010).
   PubMed Web of Science ®Google Scholar
• Daigle SR , OlhavaEJ, TherkelsenCAet al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20(1) , 53–65 (2011).
   PubMed Web of Science ®Google Scholar
• Kikuchi J , WadaT, ShimizuRet al. Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma. Blood 116(3) , 406–417 (2010).
   PubMed Web of Science ®Google Scholar
• Belinsky SA , GrimesMJ, PicchiMAet al. Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res. 71(2) , 454–462 (2011).
   PubMed Web of Science ®Google Scholar
• Stathis A , HotteSJ, ChenEXet al. Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin‘s lymphomas. Clin. Cancer Res. 17(6) , 1582–1590 (2011).
   PubMed Web of Science ®Google Scholar
• Lin J , GilbertJ, RudekMAet al. A Phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin. Cancer Res. 15(19) , 6241–6249 (2009).
   PubMed Web of Science ®Google Scholar
• He LZ , TolentinoT, GraysonPet al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J. Clin. Invest. 108(9) , 1321–1330 (2001).
   PubMed Web of Science ®Google Scholar
• Ablain J , de The H. Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood117(22) , 5795–5802 (2011).
   PubMed Web of Science ®Google Scholar
• Bolden JE , PeartMJ, JohnstoneRW. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug. Discov.5(9) , 769–784 (2006).
   PubMed Web of Science ®Google Scholar
• Kanzaki M , KakinumaH, KumazawaTet al. Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells. Oncol. Rep. 17(4) , 761–767 (2007).
   PubMed Web of Science ®Google Scholar
• Appleton K , MackayHJ, JudsonIet al. Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J. Clin. Oncol. 25(29) , 4603–4609 (2007).
   PubMed Web of Science ®Google Scholar
• George RE , LahtiJM, AdamsonPCet al. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children‘s Oncology Group study. Pediatr. Blood Cancer 55(4) , 629–638 (2010).
   PubMed Web of Science ®Google Scholar
• Soriano AO , YangH, FaderlSet al. 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(7) , 2302–2308 (2007).
   PubMed Web of Science ®Google Scholar
• Badros A , BurgerAM, PhilipSet al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin. Cancer Res. 15(16) , 5250–5257 (2009).
   PubMed Web of Science ®Google Scholar
• Mazumder A , VesoleDH, JagannathS. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice. Clin. Lymphoma Myeloma Leuk.10(2) , 149–151 (2010).
   PubMed Web of Science ®Google Scholar
• Sekeres MA , O‘KeefeC, ListAFet al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am. J. Hematol. 86(1) , 102–103 (2011).
   PubMed Web of Science ®Google Scholar
• Qin T , JelinekJ, SiJ, ShuJ, IssaJP. Mechanisms of resistance to 5-aza-2´-deoxycytidine in human cancer cell lines. Blood113(3) , 659–667 (2009).
   PubMed Web of Science ®Google Scholar
• Fantin VR , LobodaA, PaweletzCPet al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Cancer Res. 68(10) , 3785–3794 (2008).
   PubMed Web of Science ®Google Scholar
• Lindemann RK , NewboldA, WhitecrossKFet al. Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc. Natl Acad. Sci. USA 104(19) , 8071–8076 (2007).
   PubMed Web of Science ®Google Scholar
• Shao W , GrowneyJD, FengYet al. Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: defining molecular mechanisms of resistance. Int. J. Cancer 127(9) , 2199–2208 (2010).
   PubMed Web of Science ®Google Scholar
• Khan O , FotheringhamS, WoodVet al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc. Natl Acad. Sci. USA 107(14) , 6532–6537 (2010).
   PubMed Web of Science ®Google Scholar
• Fotheringham S , EppingMT, StimsonLet al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 15(1) , 57–66 (2009).
   PubMed Web of Science ®Google Scholar
• Itzykson R , KosmiderO, CluzeauTet al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25(7) , 1147–1152 (2011).
   PubMed Web of Science ®Google Scholar
• Burbury KL , BishtonMJ, JohnstoneRW, DickinsonMJ, SzerJ, PrinceHM. MLL-aberrant leukemia: complete cytogenetic remission following treatment with a histone deacetylase inhibitor (HDACi). Ann. Hematol.90(7) , 847–849 (2011).
   PubMed Web of Science ®Google Scholar
• Zender L , XueW, ZuberJet al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135(5) , 852–864 (2008).
   PubMed Web of Science ®Google Scholar
• Frew AJ , LindemannRK, MartinBPet al. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist. Proc. Natl Acad. Sci. USA 105(32) , 11317–11322 (2008).
   PubMed Web of Science ®Google Scholar
• Christiansen AJ , WestA, BanksKMet al. Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc. Natl Acad. Sci. USA 108(10) , 4141–4146 (2011).
   PubMed Web of Science ®Google Scholar
• Whitecross KF , AlsopAE, CluseLAet al. Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. Blood 113(9) , 1982–1991 (2009).
   PubMed Web of Science ®Google Scholar
• Zuber J , RadtkeI, PardeeTSet al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 23(7) , 877–889 (2009).
   PubMed Web of Science ®Google Scholar
• Odenike OM , AlkanS, SherDet al. Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia. Clin. Cancer Res. 14(21) , 7095–7101 (2008).
   PubMed Web of Science ®Google Scholar
• Fenaux P , MuftiGJ, Hellstrom-LindbergEet al. 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(3) , 223–232 (2009).
   PubMed Web of Science ®Google Scholar
• Silverman LR , MckenzieDR, PetersonBLet al. 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(24) , 3895–3903 (2006).
   PubMed Web of Science ®Google Scholar
• Kantarjian H , IssaJP, RosenfeldCSet al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a Phase III randomized study. Cancer 106(8) , 1794–1803 (2006).
   PubMed Web of Science ®Google Scholar
• Lubbert M , SuciuS, BailaLet al. 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(15) , 1987–1996 (2011).
   PubMed Web of Science ®Google Scholar
• Aribi A , BorthakurG, RavandiFet al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer 109(4) , 713–717 (2007).
   PubMed Web of Science ®Google Scholar
• Stewart DJ , IssaJP, KurzrockRet al. Decitabine effect on tumor global DNA methylation and other parameters in a Phase I trial in refractory solid tumors and lymphomas. Clin. Cancer Res. 15(11) , 3881–3888 (2009).
   PubMed Web of Science ®Google Scholar
• Winquist E , KnoxJ, AyoubJPet al. Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group Investigational New Drug study. Invest. New Drugs 24(2) , 159–167 (2006).
   PubMed Web of Science ®Google Scholar
• Reid T , ValoneF, LiperaWet al. Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer 45(3) , 381–386 (2004).
   PubMed Web of Science ®Google Scholar
• Tarasenko N , Kessler-IceksonG, BoerPet al. The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity. Invest. New Drugs DOI: 10.1007/s10637-010-9542-z (2010) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Ramalingam SS , BelaniCP, RuelCet al. Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J. Thorac. Oncol. 4(1) , 97–101 (2009).
   PubMed Web of Science ®Google Scholar
• Gimsing P , HansenM, KnudsenLMet al. A Phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur. J. Haematol. 81(3) , 170–176 (2008).
   PubMed Web of Science ®Google Scholar
• Ryan QC , HeadleeD, AcharyaMet al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J. Clin. Oncol. 23(17) , 3912–3922 (2005).
   PubMed Web of Science ®Google Scholar
• Kummar S , GutierrezM, GardnerERet al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin. Cancer Res. 13(18 Pt 1) , 5411–5417 (2007).
   PubMed Web of Science ®Google Scholar
• Gore L , RothenbergML, O‘BryantCLet al. A Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin. Cancer Res. 14(14) , 4517–4525 (2008).
   PubMed Web of Science ®Google Scholar
• Gojo I , JiemjitA, TrepelJBet al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109(7) , 2781–2790 (2007).
   PubMed Web of Science ®Google Scholar
• Galli M , SalmoiraghiS, GolayJet al. A Phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann. Hematol. 89(2) , 185–190 (2010).
   PubMed Web of Science ®Google Scholar
• Tan J , CangS, MaY, PetrilloRL, LiuD. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J. Hematol. Oncol.3 , 5 (2010).
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G , AssoulineS, CortesJet al. Phase I study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112(4) , 981–989 (2008).
   PubMed Web of Science ®Google Scholar
• Giles F , FischerT, CortesJet al. A Phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin. Cancer Res. 12(15) , 4628–4635 (2006).
   PubMed Web of Science ®Google Scholar
• Byrd JC , MarcucciG, Parthun Mr et al. A Phase I and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood105(3) , 959–967 (2005).
   PubMed Web of Science ®Google Scholar
• Itoh Y , SuzukiT, MiyataN. Isoform-selective histone deacetylase inhibitors. Curr. Pharm. Des.14(6) , 529–544 (2008).
   PubMed Web of Science ®Google Scholar
• Marshall JL , RizviN, KauhJet al. A Phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J. Exp. Ther. Oncol. 2(6) , 325–332 (2002).
   PubMedGoogle Scholar
• Sandor V , BakkeS, RobeyRWet al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin. Cancer Res. 8(3) , 718–728 (2002).
   PubMed Web of Science ®Google Scholar
• Klimek VM , FircanisS, MaslakPet al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin. Cancer Res. 14(3) , 826–832 (2008).
   PubMed Web of Science ®Google Scholar
• Kelly WK , RichonVM, O‘ConnorOet al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 9(10 Pt 1) , 3578–3588 (2003).
   PubMed Web of Science ®Google Scholar
• O‘Connor OA , HeaneyML, SchwartzLet al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 24(1) , 166–173 (2006).
   PubMed Web of Science ®Google Scholar
• Mann BS , JohnsonJR, HeKet al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin. Cancer Res. 13(8) , 2318–2322 (2007).
   PubMed Web of Science ®Google Scholar
• Galanis E , JaeckleKA, MaurerMJet al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J. Clin. Oncol. 27(12) , 2052–2058 (2009).
   PubMed Web of Science ®Google Scholar
• Cang S , MaY, LiuD. New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer. J. Hematol. Oncol.2 , 22 (2009).
   PubMed Web of Science ®Google Scholar
• Ramalingam SS , PariseRA, RamanathanRKet al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin. Cancer Res. 13(12) , 3605–3610 (2007).
   PubMed Web of Science ®Google Scholar
• Raffoux E , CrasA, RecherCet al. Phase II 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(1) , 34–42 (2010).
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G , KantarjianHM, Sanchez-GonzalezBet al. Phase I/II study of the combination of 5-aza-2´-deoxycytidine with valproic acid in patients with leukemia. Blood 108(10) , 3271–3279 (2006).
   PubMed Web of Science ®Google Scholar
• Blum W , KlisovicRB, HackansonBet al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J. Clin. Oncol. 25(25) , 3884–3891 (2007).
   PubMed Web of Science ®Google Scholar
• Beumer JH , PariseRA, NewmanEMet al. Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2´-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother. Pharmacol. 62(2) , 363–368 (2008).
   PubMed Web of Science ®Google Scholar
• Guo D , MyrdalPB, KarlageKLet al. Stability of 5-fluoro-2´-deoxycytidine and tetrahydrouridine in combination. AAPS PharmSciTech. 11(1) , 247–252 (2010).
   PubMed Web of Science ®Google Scholar
• Candelaria M , Gallardo-RinconD, ArceCet al. A Phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann. Oncol. 18(9) , 1529–1538 (2007).
   PubMed Web of Science ®Google Scholar
• Munster P , MarchionD, BicakuEet al. Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J. Clin. Oncol. 25(15) , 1979–1985 (2007).
   PubMed Web of Science ®Google Scholar

▪ Websites

• Clinical Trial Database of the National Cancer Institute www.cancer.gov
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• Clinical Trial Database of the NIH www.clinicaltrials.gov
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