Six (or More) Drugs in Search of a Mechanism: DNA Methyltransferase and Histone Deacetylase Inhibitors in the Treatment of Myelodysplastic Syndromes

The clinical activity of the DNA methyltransferase inhibitors 5-azacitidine and 2′-deoxy-5-azacytidine in myelodysplastic syndromes (MDS) suggests that epigenetic modulation of gene transcription may play an important pathogenetic role in the development and expression of these diseases. Approximately 50% of patients treated with these compounds experience hematologic improvement, making these the most active single agents for unselected patients with MDS. Responses include complete and partial hematologic responses. Two randomized trials have shown that the use of these drugs significantly alters the natural history of MDS compared with supportive care. Histone deacetylase inhibitors, which may also impact the expression of genes through epigenetic mechanisms, seem to have measurable activity in MDS in preliminary studies. Histone deacetylase inhibitors are most likely used in combination with other agents, including DNA methyltransferase inhibitors. Despite the clinical activity of these classes of drugs, there is no conclusive evidence that their clinical activity is attributable to their impact on the epigenome. Such information will be critical in the development of more effective congeners and drug combinations in ongoing attempts to improve the outcome of patients with MDS.

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Correspondence: Steven D. Gore, MD, 1650 Orleans Street, Baltimore, Maryland 21231. E-mail: Steven.Gore@Jhu.edu

References

  • 1.

    JonesPABaylinSB. The fundamental role of epigenetic events in cancer. Nat Rev Genet2002;3:415428.

  • 2.

    RiceJCAllisCD. Code of silence. Nature2001;414:258261.

  • 3.

    ListAKurtinSRoeDJ. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med2005;352:549557.

  • 4.

    Von HoffDDSlavikMMuggiaFM. 5-Azacytidine. A new anti-cancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med1976;85:237245.

    • Search Google Scholar
    • Export Citation
  • 5.

    MomparlerRLBouchardJOnettoN. 5-aza-2′-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation. Leuk Res1984;8:181185.

    • Search Google Scholar
    • Export Citation
  • 6.

    JonesPATaylorSM. Cellular differentiation, cytidine analogs and DNA methylation. Cell1980;20:8593.

  • 7.

    SchmelzKSattlerNWagnerM. Induction of gene expression by 5-Aza-2′-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms. Leukemia2005;19:103111.

    • Search Google Scholar
    • Export Citation
  • 8.

    SchmelzKWagnerMDorkenBTammI. 5-Aza-2′-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer2005;114:683695.

    • Search Google Scholar
    • Export Citation
  • 9.

    Schneider-StockRDiab-AssefMRohrbeckA. 5-Aza-cytidine is a potent inhibitor of DNA methyltransferase 3a and induces apoptosis in HCT-116 colon cancer cells via Gadd45- and p53-dependent mechanisms. J Pharmacol Exp Ther2005;312:525536.

    • Search Google Scholar
    • Export Citation
  • 10.

    ZhuWGHilemanTKeY. 5-aza-2′-deoxycytidine activates the p53/p21Waf1/Cip1 pathway to inhibit cell proliferation. J Biol Chem2004;279:1516115166.

    • Search Google Scholar
    • Export Citation
  • 11.

    CharacheSDoverGSmithK. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta globin gene complex. Proc Natl Acad Sci USA1983;80:48424846.

    • Search Google Scholar
    • Export Citation
  • 12.

    DoverGCharacheSBoyerSH. 5-azacytidine increased HbF production and reduces anemia in sickle cell disease. Dose-response analysis of subcutaneous and oral dosing regimens. Blood1985;66:532.

    • Search Google Scholar
    • Export Citation
  • 13.

    LeyTDeSimoneJAnagnouNP. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl J Med1982;307:14691475.

    • Search Google Scholar
    • Export Citation
  • 14.

    SilvermanLRHollandJFWeinbergRS. Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia1993;7[suppl 1]:2129.

    • Search Google Scholar
    • Export Citation
  • 15.

    SilvermanLHollandJFDemakosEP. Azacitidine in myelodysplastic syndromes: CALGB studies 8421 and 8921. Ann Hematol1994;68.

  • 16.

    SilvermanLRDemakosEPPetersonBL. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol2002;20:24292440.

    • Search Google Scholar
    • Export Citation
  • 17.

    KornblithABHerndonJESilvermanLR. 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 Oncol2002;20:24412452.

    • Search Google Scholar
    • Export Citation
  • 18.

    WijermansPWKrulderJWHuijgensPC. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia1997;11[suppl 1]: 1923.

    • Search Google Scholar
    • Export Citation
  • 19.

    WijermansPLubbertMVerhoefG. 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 Oncol2000;18:956962.

    • Search Google Scholar
    • Export Citation
  • 20.

    LubbertMWijermansPKunzmannR. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol2001;114:349357.

    • Search Google Scholar
    • Export Citation
  • 21.

    GreenbergPCoxCLeBeauMM. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood1997;89:20792088.

  • 22.

    SabaHIWijermansPW. Decitabine in myelodysplastic syndromes. Semin Hematol2005;42[2 suppl 2]:2331.

  • 23.

    KantarjianHMIssaJP. Decitabine dosing schedules. Semin Hematol2005;42[suppl 2]:1722.

  • 24.

    PlagemannPGBehrensMAbrahamD. Metabolism and cytotoxicity of 5-azacytidine in cultured Novikoff rat hepatoma and P388 mouse leukemia cells and their enhancement by preincubation with pyrazofurin. Cancer Res1978;38:24582466.

    • Search Google Scholar
    • Export Citation
  • 25.

    RudekMAZhaoMHeP. Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J Clin Oncol2005;23:39063911.

    • Search Google Scholar
    • Export Citation
  • 26.

    MarcucciGSilvermanLEllerM. Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol2005;45:597602.

    • Search Google Scholar
    • Export Citation
  • 27.

    DaskalakisMNguyenTTNguyenC. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood2002;100:29572964.

    • Search Google Scholar
    • Export Citation
  • 28.

    CameronEEBaylinSBHermanJG. P15INK4b CpG island methylation is heterogeneous in primary acute leukemia and suggests density as a critical factor in transcriptional silencing. Blood(in press).

    • Search Google Scholar
    • Export Citation
  • 29.

    HermanJGCivinCIIssaJP. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Canc Res1997;57:837841.

    • Search Google Scholar
    • Export Citation
  • 30.

    HermanJGJenJMerloA. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15(INK4B). Cancer Res1996;56:722727.

    • Search Google Scholar
    • Export Citation
  • 31.

    QuesnelBGuillermGVereecqueR. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood1998;91:29852990.

    • Search Google Scholar
    • Export Citation
  • 32.

    IssaJPGarcia-ManeroGGilesFJ. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood2004;103:16351640.

    • Search Google Scholar
    • Export Citation
  • 33.

    YangASEstecioMRDoshiK. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res2004;32:e38.

    • Search Google Scholar
    • Export Citation
  • 34.

    MundCHackansonBStresemannC. Characterization of DNA demethylation effects induced by 5-Aza-2′-deoxycytidine in patients with myelodysplastic syndrome. Cancer Res2005;65:70867090.

    • Search Google Scholar
    • Export Citation
  • 35.

    RosatoRRGrantS. Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets2005;9:809824.

  • 36.

    NovogrodskyADvirARavidA. Effect of polar organic compounds on leukemic cells. Butyrate-induced partial remission of acute myelogenous leukemia in a child. Cancer1983;51:914.

    • Search Google Scholar
    • Export Citation
  • 37.

    GoreSDSamidDWengLJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res1997;3:17551762.

    • Search Google Scholar
    • Export Citation
  • 38.

    DiGiuseppeJAWengLJYuKH. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: Structure-Function Analysis. Leukemia1999;13:12431253.

    • Search Google Scholar
    • Export Citation
  • 39.

    GoreSDWengLJZhaiS. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res2001;7:23302339.

    • Search Google Scholar
    • Export Citation
  • 40.

    YuKHWengLJFuSGoreSD. Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all trans-retinoic acid. Leukemia2000;13:12581265.

    • Search Google Scholar
    • Export Citation
  • 41.

    GoreSDWengLJFiggWD. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res2002;8:963970.

    • Search Google Scholar
    • Export Citation
  • 42.

    GottlicherMMinucciSZhuP. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J2001;20:69696978.

    • Search Google Scholar
    • Export Citation
  • 43.

    GurvichNTsygankovaOMMeinkothJLKleinPS. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res2004;64:10791086.

    • Search Google Scholar
    • Export Citation
  • 44.

    KuendgenAStruppCAivadoM. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood2004;104:12661269.

    • Search Google Scholar
    • Export Citation
  • 45.

    GoreSDCarducciMA. Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin Invest Drugs2000;9:29232934.

    • Search Google Scholar
    • Export Citation
  • 46.

    MinucciSPelicciPG. Retinoid receptors in health and disease: co-regulators and the chromatin connection. Semin Cell Dev Biol1999;10:215225.

    • Search Google Scholar
    • Export Citation
  • 47.

    BreitmanTRHeR. Combinations of retinoic acid with either sodium butyrate, dimethyl sulfoxide, or hexamethylene bisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL60. Cancer Res1990;60:62686273.

    • Search Google Scholar
    • Export Citation
  • 48.

    TrusMRYangLSuarezSF. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia2005;19:11611168.

    • Search Google Scholar
    • Export Citation
  • 49.

    WarrellRPJrHeLZRichonV. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. JNCI1998;90:16211625.

    • Search Google Scholar
    • Export Citation
  • 50.

    RaffouxEChaibiPDombretHDegosL. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica2005;90:986988.

    • Search Google Scholar
    • Export Citation
  • 51.

    PilatrinoCCilloniDMessaE. Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer2005;104:101109.

    • Search Google Scholar
    • Export Citation
  • 52.

    NanXNgHHJohnsonCA. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature1998;393:386389.

    • Search Google Scholar
    • Export Citation
  • 53.

    CameronEEBachmanKEMyohanenS. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet1999;21:103107.

    • Search Google Scholar
    • Export Citation
  • 54.

    Garcia-ManeroGGoreSD. Future directions for the use of hypomethylating agents. Semin Hematol2005;42(suppl 2): 5059.

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