Epigenetic therapy of cancer: Past, present and future

Nature Reviews Drug Discovery

Volumn 5, Issue 1, 2006, Pages 37-50

  Yoo, Christine B ^a   Jones, Peter A ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [N (2 HYDROXYETHYL) N [2 (3 INDOLYL)ETHYL]AMINOMETHYL]CINNAMOHYDROXAMIC ACID; 5 AZA 2' DEOXYCYTIDINE; 5,6 DIHYDROAZACITIDINE; 6 (1,3 DIOXO 1H,3H BENZO[DE]ISOQUINOLIN 2 YL) N HYDROXYHEXANAMIDE; ANTINEOPLASTIC AGENT; APICIDIN; AZACITIDINE; BENZAMIDE DERIVATIVE; BUTYRIC ACID; DEPSIPEPTIDE; EPIGALLOCATECHIN GALLATE; FLUCYTOSINE DEOXYRIBOSIDE; FR 901228; HYDRALAZINE; HYDROXAMIC ACID DERIVATIVE; LDH 589; MG 98; NUCLEOSIDE ANALOG; OXAMFLATIN; PDX 101; PROCAINAMIDE; PROCAINE; RETINOIC ACID; RG 108; TRIBUTYRIN; TRICHOSTATIN A; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID; VORINOSTAT; ZEBULARINE; HISTONE DEACETYLASE;

ACETYLATION; ACUTE MYELOBLASTIC LEUKEMIA; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CHEMOTHERAPY; CANCER GENETICS; CANCER INHIBITION; CANCER PREVENTION; CANCER THERAPY; CARCINOGENESIS; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL TRIAL; COLORECTAL CANCER; CYTOTOXICITY; DNA METHYLATION; DNA REPLICATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENTIATION; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG TARGETING; EPIGENETICS; GENE EXPRESSION REGULATION; GENE SILENCING; GENETIC SCREENING; HEMATOLOGIC DISEASE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; KIDNEY CARCINOMA; LOW DRUG DOSE; LYMPHOMA; MAXIMUM TOLERATED DOSE; MUTAGENICITY; MYELODYSPLASIA; NONHUMAN; OVARY CANCER; PLEIOTROPY; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN METHYLATION; PROTEIN PROTEIN INTERACTION; QUANTITATIVE ANALYSIS; RECEPTOR BINDING; REVIEW; SOLID TUMOR; STRUCTURE ACTIVITY RELATION; T CELL LYMPHOMA; TREATMENT OUTCOME; UTERINE CERVIX CANCER; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; GENETIC EPIGENESIS; GENETICS; NEOPLASM;

ANIMALS; ANTINEOPLASTIC AGENTS; DNA METHYLATION; EPIGENESIS, GENETIC; HISTONE DEACETYLASES; HUMANS; MOLECULAR STRUCTURE; NEOPLASMS;

EID: 33644856123     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd1930     Document Type: Review

References (164)

1. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6-21 (2002).
2. Takai, D. & Jones, P. A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl Acad. Sci. USA 99, 3740-3745 (2002).
3. Fujita, N. et al. Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol. Cell Biol. 19, 6415-6426 (1999).
4. Hendrich, B. et al. Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome 10, 906-912 (1999).
5. Perini, G., Diolaiti, D., Porro, A. & Della Valle, G. In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proc. Natl Acad. Sci. USA 102, 12117-12122 (2005).
6. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074-1080 (2001).
7. Margueron, R., Trojer, P. & Reinberg, D. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163-176 (2005).
8. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110-113 (2001).
9. Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251-1262 (2004).
10. Rice, J. C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591-1598 (2003).
11. Vakoc, C. R., Mandat, S. A., Olenchock, B. A. & Blobel, G. A. Histone H3 lysine 9 methylation and HP1 gamma are associated with transcription elongation through mammalian chromatin. Mol. Cell 19, 381-391 (2005).
12. Hashimshony, T., Zhang, J., Keshet, I., Bustin, M. & Cedar, H. The role of DNA methylation in setting up chromatin structure during development. Nature Genet. 34, 187-192 (2003).
13. Chen, W. et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell 6, 387-398 (2004).
14. Hoffmann, M. J. & Schulz, W. A. Causes and consequences of DNA hypomethylation in human cancer. Biochem. Cell Biol. 83, 296-321 (2005).
15. Holst, C. R. et al. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 63, 1596-1601 (2003).
16. Cheng, J. C. et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl Cancer Inst. 95, 399-409 (2003).
17. Herranz, M. et al. The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. Blood 20 Oct 2005 [epub ahead of print].
18. Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197-205 (1995).
19. Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89-92 (1983).
20. Riggs, A. D. & Jones, P. A. 5-methylcytosine, gene regulation, and cancer. Adv. Cancer Res. 40, 1-30 (1983).
21. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).
22. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489-492 (2003).
23. Gius, D. et al. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell 6, 361-371 (2004).
24. Cheng, J. C. et al. Preferential response of cancer cells to zebularine. Cancer Cell 6, 151-158 (2004).
25. Liang, G., Gonzales, F. A., Jones, P. A., Orntoft, T. F. & Thykjaer, T. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2′-deoxycytidine. Cancer Res. 62, 961-966 (2002).
26. Costello, J. F. et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet. 24, 132-138 (2000).
27. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681-8686 (1999).
28. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853-862 (2005).
29. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391-400 (2005).
30. Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262-1266 (2005).
31. Mutskov, V. & Felsenfeld, G. Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. EMBO J. 23, 138-149 (2004).
32. Masumoto, H., Hawke, D., Kobayashi, R. & Verreault, A. A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response. Nature 436, 294-298 (2005).
33. Whetstine, J. R. et al. Regulation of tissue-specific and extracellular matrix-related genes by a class I histone deacetylase. Mol. Cell 18, 483-490 (2005).
34. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004).
35. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature (2005).
36. Garcia-Cao, M., O'Sullivan, R., Peters, A. H., Jenuwein, T. & Blasco, M. A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nature Genet. 36, 94-99 (2004).
37. Erlanson, D. A., Chen, L., and Verdine, G. L. DNA Methylation through a locally unpaired intermediate. J. Am. Chem. Soc. 115, 12583-12584 (1993).
38. Klimasauskas, S., Kumar, S., Roberts, R. J. & Cheng, X. Hhal methyltransferase flips its target base out of the DNA helix. Cell 76, 357-369 (1994).
39. Wu, J. C. & Santi, D. V. Kinetic and catalytic mechanism of Hhal methyltransferase. J. Biol. Chem. 262, 4778-4786 (1987).
40. Santi, D. V., Garrett, C. E. & Barr, P. J. On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell 33, 9-10 (1983).
41. Santi, D. V., Norment, A. & Garrett, C. E. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc. Natl Acad. Sci. USA 81, 6993-6997 (1984).
42. Zhou, L. et al. Zebularine: A novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J. Mol. Biol. 321, 591-599 (2002).
43. Ghoshal, K. et 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, 4727-4741 (2005).
44. Schermelleh, L. et al. Trapped in action: Direct visualization of DNA methyltransferase activity in living cells. Nature Methods 2, 751-756 (2005).
45. Pliml, J. & Sorm, F. Synthesis of 2′-deoxy-D-ribofuranosyl-5-azacytosine. Coll Czech Chem Commun 29, 2576-2577 (1964).
46. Sorm, F. & Vesely, J. Effect of 5-aza-2′-deoxycytidine against leukemic and hematopoietic tissues in AKR mice. Neoplasma 15, 339-343 (1968).
47. Jones, P. A. & Taylor, S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85-93 (1980).
48. Taylor, S. M. & Jones, P. A. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 17, 771-779 (1979).
49. Lin, K. T., Momparler, R. L. & Rivard, G. E. High-performance liquid chromatographic analysis of chemical stability of 5-aza-2′-deoxycytidine. J. Pharm. Sci. 70, 1228-1232 (1981).
50. Notari, R. E. & DeYoung, J. L. Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions. J. Pharm. Sci. 64, 1148-1157 (1975).
51. Kaminskas, E. et al. Approval summary: Azacitidine for treatment of myelodysplastic syndrome subtypes. Clin. Cancer Res. 11, 3604-3608 (2005).
52. Issa, J. P. et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103, 1635-1640 (2004).
53. Issa, J. P. et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J. Clin. Oncol. 23, 3948-3956 (2005).
54. Lubbert, M. et al. Nonclonal neutrophil responses after successful treatment of myelodysplasia with low-dose 5-aza-2′-deoxycytidine (decitabine). Leuk. Res. 28, 1267-1271 (2004).
55. Aparicio, A. et al. Phase I trial of continuous infusion 5-aza-2′-deoxycytidine. Cancer Chemother. Pharmacol. 51, 231-239 (2003).
56. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103-107 (1999).
57. Rudek, M. A. et al. Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J. Clin. Oncol. 23, 3906-3911 (2005).
58. Beisler, J. A., Abbasi, M. M. & Driscoll, J. S. Dihydro-5-azacytidine hydrochloride, a biologically active and chemically stable analog of 5-azacytidine. Cancer Treat. Rep. 60, 1671-1674 (1976).
59. Beisler, J. A., Abbasi, M. M., Kelley, J. A. & Driscoll, J. S. Synthesis and antitumor activity of dihydro-5-azacytidine, a hydrolytically stable analogue of 5-azacytidine. J. Med. Chem. 20, 806-812 (1977).
60. Presant, C. A., Coulter, D., Valeriote, F. & Vietti, T. J. Contrasting cytotoxicity kinetics of 5-azacytidine and dihydro-5-azacytidine hydrochloride in L1210 leukemia in mice. J. Natl Cancer Inst. 66, 1151-1154 (1981).
61. Stopper, H., Korber, C., Gibis, P., Spencer, D. L. & Caspary, W. J. Micronuclei induced by modulators of methylation: Analogs of 5-azacytidine. Carcinogenesis 16, 1647-1650 (1995).
62. Antonsson, B. E., Avramis, V. I., Nyce, J. & Holcenberg, J. S. Effect of 5-azacytidine and congeners on DNA methylation and expression of deoxycytidine kinase in the human lymphoid cell lines CCRF/CEM/0 and CCRF/CEM/dCk-1. Cancer Res. 47, 3672-3678 (1987).
63. Kees, U. R. & Avramis, V. I. Biochemical pharmacology and DNA methylation studies of arabinosyl 5-azacytidine and 5, 6-dihydro-5-azacytidine in two human leukemia cell lines PER-145 and PER-163. Anticancer Drugs 6, 303-310 (1995).
64. Powell, W. C. & Avramis, V. I. Biochemical pharmacology of 5, 6-dihydro-5-azacytidine (DHAC) and DNA hypomethylation in tumor (L1210)-bearing mice. Cancer Chemother. Pharmacol. 21, 117-121 (1988).
65. Curt, G. A. et al. A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880). Cancer Res. 45, 3359-3363 (1985).
66. Eidinoff, M. L., Rich, M. A. & Perez, A. G. Growth inhibition of a human tumor cell strain by 5-fluorocytidine and 5-fluoro-2′-deoxycytidine: reversal studies. Cancer Res. 19, 638-642 (1959).
67. Chen, L. et al. Direct identification of the active-site nucleophile in a DNA (cytosine-5)-methyltransferase. Biochemistry 30, 11018-11025 (1991).
68. Barchi, J. J., Jr. et al. Improved synthesis of zebularine [1-(β-D-ribofuranosyl)-dihydropyrimidin-2-one] nucleotides as inhibitors of human deoxycytidylate deaminase. J. Enzyme Inhib. 9, 147-162 (1995).
69. Frick, L., Yang, C., Marquez, V. E. & Wolfenden, R. Binding of pyrimidin-2-one ribonucleoside by cytidine deaminase as the transition-state analogue 3,4-dihydrouridine and the contribution of the 4-hydroxyl group to its binding affinity. Biochemistry 28, 9423-9430 (1989).
70. Kim, C. H., Marquez, V. E., Mao, D. T., Haines, D. R. & McCormack, J. J. Synthesis of pyrimidin-2-one nucleosides as acid-stable inhibitors of cytidine deaminase. J. Med. Chem. 29, 1374-1380 (1986).
71. Laliberte, J., Marquez, V. E. & Momparler, R. L. Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2′-deoxycytidine by human cytidine deaminase. Cancer Chemother. Pharmacol. 30, 7-11 (1992).
72. Driscoll, J. S. et al. Antitumor properties of 2(1H)-pyrimidinone riboside (zebularine) and its fluorinated analogues. J. Med. Chem. 34, 3280-3284 (1991).
73. Lee, G., Wolff, E. & Miller, J. H. Mutagenicity of the cytidine analog zebularine in Escherichia coli. DNA Repair (Amst) 3, 155-161 (2004).
74. Holleran, J. L. et al. Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the DNA methyltransferase inhibitor, zebularine. Clin. Cancer Res. 11, 3862-3868 (2005).
75. Brueckner, B. et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. 65, 6305-6311 (2005).
76. Schuebel, K. & Baylin, S. In living color: DNA methyltransferase caught in the act. Nature Methods 2, 736-738 (2005).
77. Davis, A. J. et al. Phase I and pharmacology study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks. Invest. New Drugs 21, 85-97 (2003).
78. Stewart, D. J. et al. A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. Ann. Oncol. 14, 766-774 (2003).
79. Pina, I. C. et al. Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J. Org. Chem. 68, 3866-3873 (2003).
80. Fang, M. Z. et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63, 7563-7570 (2003).
81. Alikhani-Koopaei, R., Fouladkou, F., Frey, F. J. & Frey, B. M. Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression. J. Clin. Invest. 114, 1146-1157 (2004).
82. Cornacchia, E. et al. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J. Immunol. 140, 2197-2200 (1988).
83. Lin, X. et al. Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide. Cancer Res. 61, 8611-8616 (2001).
84. Segura-Pacheco, B. et al. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin. Cancer Res. 9, 1596-1603 (2003).
85. Villar-Garea, A., Fraga, M. F., Espada, J. & Esteller, M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res 63, 4984-4989 (2003).
86. Zambrano, P. et al. A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer 5, 44 (2005).
87. Chuang, J. C. et al. Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine. Mol. Cancer Ther. 4, 1515-1520 (2005).
88. Rocchi, P. et al. p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol. Rep. 13, 1139-1144 (2005).
89. Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med. 11, 77-84 (2005).
90. Peart, M. J. et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc. Natl Acad. Sci. US4 102, 3697-3702 (2005).
91. Shetty, S. et al. Transcription factor NF-κB differentially regulates death receptor 5 expression involving histone deacetylase 1. Mol. Cell Biol. 25, 5404-5416 (2005).
92. Dai, Y., Rahmani, M., Dent, P. & Grant, S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol. Cell Biol. 25, 5429-5444 (2005).
93. Duan, H., Heckman, C. A. & BOX er, L. M. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol. Cell Biol. 25, 1608-1619 (2005).
94. Michaelis, M. et al. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol. Pharmacol. 65, 520-527 (2004).
95. Joseph, J. et al. Expression profiling of sodium butyrate (NaB)-treated cells: Identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB. Oncogene 23, 6304-6315 (2004).
96. Qiu, L. et al. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol. Biol Cell. 11, 2069-2083 (2000).
97. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595-606 (1997).
98. Chen, L. F. & Greene, W. C. Regulation of distinct biological activities of the NF-κB transcription factor complex by acetylation. J. Mol. Med. 81, 549-557 (2003).
99. Stadtman, E. R. & Barker, H. A. Fatty acid synthesis by enzyme preparations of Clostridium kluyveri; a consideration of postulated 4-carbon intermediates in butyrate synthesis. J. Biol. Chem. 181, 221-235 (1949).
100. Gottlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969-6978 (2001).
101. Candido, E. P., Reeves, R. & Davie, J. R. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14, 105-113 (1978).
102. Sealy, L. & Chalkley, R. The effect of sodium butyrate on histone modification. Cell 14, 115-121 (1978).
103. 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 90, 986-988 (2005).
104. Yang, H., Hoshino, K., Sanchez-Gonzalez, B., Kantarjian, H. & Garcia-Manero, G. Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk. Res. 29, 739-748 (2005).
105. Kramer, O. H. et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 22, 3411-3420 (2003).
106. Perrine, S. P. et al. Butyrate derivatives. New agents for stimulating fetal globin production in the β-globin disorders. Am. J. Pediatr. Hematol. Oncol. 16, 67-71 (1994).
107. van de Mark, K., Chen, J. S., Steliou, K., Perrine, S. P. & Faller, D. V. Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines. J. Cell. Physiol. 194, 325-340 (2003).
108. Yoshida, M., Kijima, M., Akita, M. & Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174-17179 (1990).
109. Kelly, W. K. et al. Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 9, 3578-3588 (2003).
110. Kelly, W. K. et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 23, 3923-3931 (2005).
111. Finnin, M. S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188-193 (1999).
112. Monneret, C. Histone deacetylase inhibitors. Eur J. Med. Chem. 40, 1-13 (2005).
113. Giles, F. J. et al. A phase I/II study of intravenous LBH589, a novel histone deacetylase (HDAC) inhibitor, in patients (pts) with advanced hematologic malignancies. Blood 104, 499A (2004).
114. Remiszewski, S. W. et al. N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4- (2-hydroxyethyl)[2-(1H-indol-3-yl)ethy l]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824). J. Med. Chem. 46, 4609-4624 (2003).
115. Kijima, M., Yoshida, M., Sugita, K., Horinouchi, S. & Beppu, T. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J. Biol. Chem. 268, 22429-22435 (1993).
116. Byrd, J. C. et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105, 959-967 (2005).
117. Marshall, J. L. et al. A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J. Exp. Ther. Oncol. 2, 325-332 (2002).
118. Piekarz, R. L. et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report. Blood 98, 2865-2868 (2001).
119. Sandor, V. et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin. Cancer Res. 8, 718-728 (2002).
120. Remiszewski, S. W. The discovery of NVP-LAQ824: From concept to clinic. Curr. Med. Chem. 10, 2393-2402 (2003).
121. Singh, S. B. et al. Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions. Org. Lett 3, 2815-2818 (2001).
122. Furumai, R. et al. Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc. Natl Acad. Sci. USA 98, 87-92 (2001).
123. Jose, B. et al. Novel histone deacetylase inhibitors: Cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones. Bioorg. Med. Chem. Lett. 14, 5343-5346 (2004).
124. Nishino, N. et al. Cyclic tetrapeptides bearing a sulfhydryl group potently inhibit histone deacetylases. Org. Lett. 5, 5079-5082 (2003).
125. Nishino, N. et al. Synthesis and histone deacetylase inhibitory activity of cyclic tetrapeptides containing a retrohydroxamate as zinc ligand. Bioorg. Med. Chem. Lett. 14, 2427-2431 (2004).
126. Saito, A. et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl Acad. Sci. USA 96, 4592-4597 (1999).
127. Camphausen, K. et al. Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res. 64, 316-321 (2004).
128. Wang, X. F. et al. Epigenetic modulation of retinoic acid receptor β2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. Clin. Cancer Res. 11, 3535-3542 (2005).
129. Pauer, L. R. et al. Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest 22, 886-896 (2004).
130. Prakash, S. et al. Chronic oral administration of CI-994: A phase 1 study. Invest. New Drugs 19, 1-11 (2001).
131. Undevia, S. D. et al. A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine. Ann. Oncol. 15, 1705-1711 (2004).
132. Yoo, C. B., Cheng, J. C. & Jones, P. A. Zebularine: A new drug for epigenetic therapy. Biochem. Soc. Trans. 32, 910-912 (2004).
133. Pohlmann, P. et al. Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix. Am J. Clin. Oncol. 25, 496-501 (2002).
134. Schwartsmann, G. et al. 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 (2000).
135. Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253-266 (2003).
136. Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 19 Nov 2004 [epub ahead of print].
137. Kubicek, S. & Jenuwein, T. A crack in histone lysine methylation. Cell 119, 903-906 (2004).
138. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41-45 (2000).
139. Liang, G. et al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc. Natl Acad. Sci. USA 101, 7357-7362 (2004).
140. Schubeler, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263-1271 (2004).
141. Lo, W. S. et al. Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol. Cell 5, 917-926 (2000).
142. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116-120 (2001).
143. Bourc'his, D. & Bestor, T. H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96-99 (2004).
144. Bourc'his, D., Xu, G. L., Lin, C. S., Bollman, B. & Bestor, T. H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536-2539 (2001).
145. Gibbons, R. J. Histone modifying and chromatin remodelling enzymes in cancer and dysplastic syndromes. Hum. Mol. Genet. 14 (Spec. No 1), R85-R92 (2005).
146. Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily Conserved and Nonconserved Cellular Localizations and Functions of Human SIRT Proteins. Mol. Biol. Cell. 16, 4623-4635 (2005).
147. Schneider, R., Bannister, A. J. & Kouzarides, T. Unsafe SETS: Histone lysine methyltransferases and cancer. Trends Biochem. Sci. 27, 396-402 (2002).
148. Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Genet Dev. 12, 198-209 (2002).
149. Bannister, A. J. & Kouzarides, T. Reversing histone methylation. Nature 436, 1103-1106 (2005).
150. Karon, M. et al. 5-Azacytidine: A new active agent for the treatment of acute leukemia. Blood 42, 359-365 (1973).
151. Moertel, C. G., Schutt, A. J., Reitemeier, R. J. & Hahn, R. G. Phase II study of 5-azacytidine (NSC-102816) in the treatment of advanced gastrointestinal cancer. Cancer Chemother. Rep. 56, 649-652 (1972).
152. Gaynon, P. S. & Baum, E. S. Continuous infusion of 5-azacytidine as induction for acute nonlymphocytic leukemia in patients with previous exposure to 5-azacytidine. Oncology 40, 192-194 (1983).
153. Velez-Garcia, E., Vogler, W. R., Bartolucci, A. A. & Arkun, S. N. Twice weekly 5-azacytidine infusion in dissmeinated metastatic cancer: A phase II study. Cancer Treat. Rep. 61, 1675-1677 (1977).
154. Weiss, A. J. et al. Phase II study of 5-azacytidine in solid tumors. Cancer Treat. Rep. 61, 55-58 (1977).
155. Lomen, P. L., Khilanani, P. & Kessel, D. Phase I study using combination of hydroxyurea and 5-azacytidine (NSC-102816). Neoplasma 27, 101-106 (1980).
156. Nitschke, R., Land, V., Steuber, C. P. & Ragab, A. H. Low response rate to 5 aza-cytidine, vincristine, and prednisone therapy in previously treated childhood acute nonlymphocytic leukemia: A Southwest Oncology Group Study. Am. J. Pediatr. Hematol. Oncol. 3, 307-309 (1981).
157. Kornblith, A. B. et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: A Cancer and Leukemia Group B study. J. Clin. Oncol. 20, 2441-2452 (2002).
158. Silverman, L. R. et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429-2440 (2002).
159. Silverman, L. R. et al. Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7 (Suppl. 1), 21-29 (1993).
160. Momparler, R. L. et al. Pilot phase I-II study on 5-aza-2′-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Anticancer Drugs 8, 358-368 (1997).
161. Zagonel, V. et al. 5-Aza-2′-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Leukemia 7 (Suppl. 1), 30-35 (1993).
162. Samlowski, W. E. et al. 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 (2005).
163. Sarraf, S. A. & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell 15, 595-605 (2004).
164. Zgouras, D., Becker, U., Loitsch, S. & Stein, J. Modulation of angiogenesis-related protein synthesis by valproic acid. Biochem. Biophys. Res. Commun. 316, 693-697 (2004).