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

Author: Steven D. Gore MD 1
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  • 1 From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

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
  • 1.

    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415428.

  • 2.

    Rice JC, Allis CD. Code of silence. Nature 2001;414:258261.

  • 3.

    List A, Kurtin S, Roe DJ. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352:549557.

  • 4.

    Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine. A new anti-cancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 1976;85:237245.

    • Search Google Scholar
    • Export Citation
  • 5.

    Momparler RL, Bouchard J, Onetto N. 5-aza-2′-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation. Leuk Res 1984;8:181185.

    • Search Google Scholar
    • Export Citation
  • 6.

    Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980;20:8593.

  • 7.

    Schmelz K, Sattler N, Wagner M. 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. Leukemia 2005;19:103111.

    • Search Google Scholar
    • Export Citation
  • 8.

    Schmelz K, Wagner M, Dorken B, Tamm I. 5-Aza-2′-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer 2005;114:683695.

    • Search Google Scholar
    • Export Citation
  • 9.

    Schneider-Stock R, Diab-Assef M, Rohrbeck A. 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 Ther 2005;312:525536.

    • Search Google Scholar
    • Export Citation
  • 10.

    Zhu WG, Hileman T, Ke Y. 5-aza-2′-deoxycytidine activates the p53/p21Waf1/Cip1 pathway to inhibit cell proliferation. J Biol Chem 2004;279:1516115166.

    • Search Google Scholar
    • Export Citation
  • 11.

    Charache S, Dover G, Smith K. 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 USA 1983;80:48424846.

    • Search Google Scholar
    • Export Citation
  • 12.

    Dover G, Charache S, Boyer SH. 5-azacytidine increased HbF production and reduces anemia in sickle cell disease. Dose-response analysis of subcutaneous and oral dosing regimens. Blood 1985;66:532.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ley T, DeSimone J, Anagnou NP. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl J Med 1982;307:14691475.

    • Search Google Scholar
    • Export Citation
  • 14.

    Silverman LR, Holland JF, Weinberg RS. Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 1993;7[suppl 1]:2129.

    • Search Google Scholar
    • Export Citation
  • 15.

    Silverman L, Holland JF, Demakos EP. Azacitidine in myelodysplastic syndromes: CALGB studies 8421 and 8921. Ann Hematol 1994;68.

  • 16.

    Silverman LR, Demakos EP, Peterson BL. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20:24292440.

    • Search Google Scholar
    • Export Citation
  • 17.

    Kornblith AB, Herndon JE, Silverman LR. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 2002;20:24412452.

    • Search Google Scholar
    • Export Citation
  • 18.

    Wijermans PW, Krulder JW, Huijgens PC. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 1997;11[suppl 1]: 1923.

    • Search Google Scholar
    • Export Citation
  • 19.

    Wijermans P, Lubbert M, Verhoef G. 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 2000;18:956962.

    • Search Google Scholar
    • Export Citation
  • 20.

    Lubbert M, Wijermans P, Kunzmann R. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 2001;114:349357.

    • Search Google Scholar
    • Export Citation
  • 21.

    Greenberg P, Cox C, LeBeau MM. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:20792088.

  • 22.

    Saba HI, Wijermans PW. Decitabine in myelodysplastic syndromes. Semin Hematol 2005;42[2 suppl 2]:2331.

  • 23.

    Kantarjian HM, Issa JP. Decitabine dosing schedules. Semin Hematol 2005;42[suppl 2]:1722.

  • 24.

    Plagemann PG, Behrens M, Abraham D. Metabolism and cytotoxicity of 5-azacytidine in cultured Novikoff rat hepatoma and P388 mouse leukemia cells and their enhancement by preincubation with pyrazofurin. Cancer Res 1978;38:24582466.

    • Search Google Scholar
    • Export Citation
  • 25.

    Rudek MA, Zhao M, He P. Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J Clin Oncol 2005;23:39063911.

    • Search Google Scholar
    • Export Citation
  • 26.

    Marcucci G, Silverman L, Eller M. Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 2005;45:597602.

    • Search Google Scholar
    • Export Citation
  • 27.

    Daskalakis M, Nguyen TT, Nguyen C. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 2002;100:29572964.

    • Search Google Scholar
    • Export Citation
  • 28.

    Cameron EE, Baylin SB, Herman JG. 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.

    Herman JG, Civin CI, Issa JP. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Canc Res 1997;57:837841.

    • Search Google Scholar
    • Export Citation
  • 30.

    Herman JG, Jen J, Merlo A. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15(INK4B). Cancer Res 1996;56:722727.

    • Search Google Scholar
    • Export Citation
  • 31.

    Quesnel B, Guillerm G, Vereecque R. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998;91:29852990.

    • Search Google Scholar
    • Export Citation
  • 32.

    Issa JP, Garcia-Manero G, Giles FJ. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004;103:16351640.

    • Search Google Scholar
    • Export Citation
  • 33.

    Yang AS, Estecio MR, Doshi K. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 2004;32:e38.

    • Search Google Scholar
    • Export Citation
  • 34.

    Mund C, Hackanson B, Stresemann C. Characterization of DNA demethylation effects induced by 5-Aza-2′-deoxycytidine in patients with myelodysplastic syndrome. Cancer Res 2005;65:70867090.

    • Search Google Scholar
    • Export Citation
  • 35.

    Rosato RR, Grant S. Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets 2005;9:809824.

  • 36.

    Novogrodsky A, Dvir A, Ravid A. Effect of polar organic compounds on leukemic cells. Butyrate-induced partial remission of acute myelogenous leukemia in a child. Cancer 1983;51:914.

    • Search Google Scholar
    • Export Citation
  • 37.

    Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res 1997;3:17551762.

    • Search Google Scholar
    • Export Citation
  • 38.

    DiGiuseppe JA, Weng LJ, Yu KH. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: Structure-Function Analysis. Leukemia 1999;13:12431253.

    • Search Google Scholar
    • Export Citation
  • 39.

    Gore SD, Weng LJ, Zhai S. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 2001;7:23302339.

    • Search Google Scholar
    • Export Citation
  • 40.

    Yu KH, Weng LJ, Fu S, Gore SD. Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all trans-retinoic acid. Leukemia 2000;13:12581265.

    • Search Google Scholar
    • Export Citation
  • 41.

    Gore SD, Weng LJ, Figg WD. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 2002;8:963970.

    • Search Google Scholar
    • Export Citation
  • 42.

    Gottlicher M, Minucci S, Zhu P. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001;20:69696978.

    • Search Google Scholar
    • Export Citation
  • 43.

    Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 2004;64:10791086.

    • Search Google Scholar
    • Export Citation
  • 44.

    Kuendgen A, Strupp C, Aivado M. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 2004;104:12661269.

    • Search Google Scholar
    • Export Citation
  • 45.

    Gore SD, Carducci MA. Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin Invest Drugs 2000;9:29232934.

    • Search Google Scholar
    • Export Citation
  • 46.

    Minucci S, Pelicci PG. Retinoid receptors in health and disease: co-regulators and the chromatin connection. Semin Cell Dev Biol 1999;10:215225.

    • Search Google Scholar
    • Export Citation
  • 47.

    Breitman TR, He R. 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 Res 1990;60:62686273.

    • Search Google Scholar
    • Export Citation
  • 48.

    Trus MR, Yang L, Suarez SF. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia 2005;19:11611168.

    • Search Google Scholar
    • Export Citation
  • 49.

    Warrell RP Jr, He LZ, Richon V. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. JNCI 1998;90:16211625.

    • Search Google Scholar
    • Export Citation
  • 50.

    Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 2005;90:986988.

    • Search Google Scholar
    • Export Citation
  • 51.

    Pilatrino C, Cilloni D, Messa E. 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. Cancer 2005;104:101109.

    • Search Google Scholar
    • Export Citation
  • 52.

    Nan X, Ng HH, Johnson CA. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998;393:386389.

    • Search Google Scholar
    • Export Citation
  • 53.

    Cameron EE, Bachman KE, Myohanen S. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet 1999;21:103107.

    • Search Google Scholar
    • Export Citation
  • 54.

    Garcia-Manero G, Gore SD. Future directions for the use of hypomethylating agents. Semin Hematol 2005;42(suppl 2): 5059.

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