DNA methyltransferase inhibitors - State of the art

Annals of Oncology

Volumn 13, Issue 11, 2002, Pages 1699-1716

  Goffin, J ^a   Eisenhauer, E ^a  

^a QUEEN S UNIVERSITY   (Canada)

Author keywords

DNA methylation; DNA methyltransferase antagonists; Oligodeoxynucleotides; Tumor suppressor genes

Indexed keywords

4 PHENYLBUTYRIC ACID; 5 AZA 2' DEOXYCYTIDINE; 5,6 DIHYDROAZACITIDINE; AMSACRINE; ANTHRACYCLINE; ANTISENSE OLIGODEOXYNUCLEOTIDE; AZACITIDINE; CARBOPLATIN; CREATININE; CYTARABINE; CYTOSINE; DAUNORUBICIN; DEOXYTHIOGUANOSINE; DNA METHYLTRANSFERASE; DOXORUBICIN; ETOPOSIDE; FAZARABINE; GEMCITABINE; GUANAZOLE; METHYLTRANSFERASE INHIBITOR; MITOXANTRONE; PIRAZOFURIN; PREDNISOLONE; PREDNISONE; PROTEIN P16; TIOGUANINE; VINCRISTINE; ZORUBICIN;

ANEMIA; ANTINEOPLASTIC ACTIVITY; APATHY; BLEEDING; BODY WEIGHT DISORDER; BONE MARROW SUPPRESSION; BREAST CANCER; CARCINOMA; CARDIOTOXICITY; CHROMATIN STRUCTURE; CLINICAL TRIAL; COLON CANCER; CONFUSION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CREATININE BLOOD LEVEL; DIARRHEA; DISORIENTATION; DNA METHYLATION; DRUG EFFICACY; DRUG MECHANISM; DRUG STRUCTURE; FEVER; GASTROINTESTINAL SYMPTOM; GENE REPRESSION; GENETIC STABILITY; GRANULOCYTOPENIA; HUMAN; HYPOTENSION; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA; LIVER TOXICITY; MELANOMA; MUCOSA INFLAMMATION; NEUTROPENIA; NONHUMAN; PERITONITIS; PRIORITY JOURNAL; REVIEW; SOLID TUMOR; SOMNOLENCE; STOMATITIS; THROMBOCYTOPENIA; TRANSPOSON; TUMOR SUPPRESSOR GENE;

EID: 0036861629     PISSN: 09237534     EISSN: None     Source Type: Journal    
DOI: 10.1093/annonc/mdf314     Document Type: Review

References (193)

1. Noyer-Weidner M, Trautner TA. Methylation of DNA in prokaryotes. EXS 1993; 64: 39-108.
2. Colot V, Rossignol JL. Eukaryotic DNA methylation as an evolutionary device. Bioessays 1999; 21: 402-411.
3. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168-174.
4. Momparler RL, Eliopoulos N, Ayoub J. Evaluation of an inhibitor of DNA methylation, 5-aza-2′-deoxycytidine, for the treatment of lung cancer and the future role of gene therapy. Adv Exp Med Biol 2000; 465: 433-446.
5. Robertson KD. DNA methylation, methyltransferases and cancer. Oncogene 2001; 20: 3139-3155.
6. Yoder JA, Walsh CP, Bestor TH. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 1997; 13: 335-340.
7. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 2001; 134: 573-586.
8. Barlow DP. Gametic imprinting in mammals. Science 1995; 270: 1610-1613.
9. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992; 69: 915-926.
10. Razin A, Shemer R. DNA methylation in early development. Hum Mol Genet 1995; 4: 1751-1755.
11. Szyf M. Towards a pharmacology of DNA methylation. Trends Pharmacol Sci 2001; 22: 350-354.
12. Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 1999; 274: 33002-33010.
13. Beard C, Li E, Jaenisch R. Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dev 1995; 9: 2325-2334.
14. Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993; 366: 362-365.
15. Leonhardt H, Page AW, Weier HU, Bestor TH. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 1992; 71: 865-873.
16. Chuang LS, Ian HI, Koh TW et al. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for P21WAF1. Science 1997; 277: 1996-2000.
17. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247-257.
18. Okano M, Xie S, Li E. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res 1998; 26: 2536-2540.
19. Rhee I, Jair KW, Yen RW et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 2000; 404: 1003-1007.
20. Vertino PM, Yen RW, Gao J, Baylin SB. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol Cell Biol 1996; 16: 4555-4565.
21. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genet 1998; 19: 219-220.
22. Yoder JA, Bestor TH. A candidate mammalian DNA methyltransferase related to Pmt1p of fission yeast. Hum Mol Genet 1998; 7: 279-284.
23. Aapola U, Kawasaki K, Scott HS et al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 2000; 65: 293-298.
24. Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 1993; 3: 226-231.
25. Nan X, Campoy FJ, Bird A. MeCP2 Is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 1997; 88: 471-481.
26. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature Genet 2000; 25: 269-277.
27. Nan X, Ng HH, Johnson CA et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386-389.
28. Robertson KD, Ait-Si-Ali S, Yokochi T et al. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature Genet 2000; 25: 338-342.
29. Puget N, Torchard D, Serova-Sinilnikova OM et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res 1997; 57: 828-831.
30. Rouyer F, Simmler MC, Page DC, Weissenbach, J. A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell 1987; 51: 417-425.
31. Small K, Iber J, Warren ST. Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nature Genet 1997; 16: 96-99.
32. Wachsman JT. DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis. Mutat Res 1997; 375: 1-8.
33. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321: 209-213.
34. Jones PA, Rideout WM III, Shen JC et al. Methylation, mutation and cancer. Bioessays 1992; 14: 33-36.
35. Narayan A, Ji W, Zhang XY et al. Hypomethylation of pericentromeric DNA in breast adenocarcinomas. Int J Cancer 1998; 77: 833-838.
36. Qu GZ, Grundy PE, Narayan A, Ehrlich M. Frequent hypomethylation in Wilms' tumors of pericentromeric DNA in chromosomes 1 and 16. Cancer Genet Cytogenet 1999; 109: 34-39.
37. Qu G, Dubeau L, Narayan A et al. Satellite DNA hypomethylation versus overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential. Mutat Res 1999; 423: 91-101.
38. Florl AR, Lower R, Schmitz-Drager BJ, Schulz WA. DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas. Br J Cancer 1999; 80: 1312-1321.
39. Antequera F, Bird A. Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci USA 1993; 90: 11995-11999.
40. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366: 704-707.
41. Otterson GA, Khleif SN, Chen W et al. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of P16INK4 protein induction by 5-aza-2′-deoxycytidine. Oncogene 1995; 11: 1211-1216.
42. Herman JG, Merlo A, Mao L et al. Inactivation of the CDKN2/P16/ MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 1995; 55: 4525-4530.
43. Myohanen SK, Baylin SB, Herman JG. Hypermethylation can selectively silence individual P16ink4A alleles in neoplasia. Cancer Res 1998; 58: 591-593.
44. Nuovo GJ, Plaia TW, Belinsky SA et al. In situ detection of the hypermethylation-induced inactivation of the P16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA 1999; 96: 12754-12759.
45. Belinsky SA, Nikula KJ, Palmisano WA et 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 1998; 95: 11891-11896.
46. De Marzo AM, Marchi VL, Yang ES et al. Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. Cancer Res 1999; 59: 3855-3860.
47. Bigey P, Knox JD, Croteau S et al. Modified oligonucleotides as bona fide antagonists of proteins interacting with DNA. Hairpin antagonists of the human DNA methyltransferase. J Biol Chem 1999; 274: 4594-4606.
48. Ramchandani S, MacLeod AR, Pinard M et al. Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. Proc Natl Acad Sci USA 1997; 94: 684-689.
49. Lantry LE, Zhang Z, Crist KA et al. 5-Aza-2′-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model. Carcinogenesis 1999; 20: 343-346.
50. Covey JM, Zaharko DS. Comparison of the in vitro cytotoxicity (L1210) of 5-aza-2′-deoxycytidine with its therapeutic and toxic effects in mice. Eur J Cancer Clin Oncol 1985; 21: 109-117.
51. Piskala A, Sorm, F. Nucleic acids components and their analogues. LI. Synthesis of 1-glycosyl derivatives of 5-azauracil and 5-azacytosine. Coll Czeck Chem Commun 1964; 29: 2060-2076.
52. Pliml J, Sorm, F. Synthesis of 2′-deoxy-D-ribofuranosyl-5-azacytosine. Coll Czeck Chem Commun 1964; 29: 2576-2577.
53. Lubbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol 2000; 249: 135-164.
54. Juttermann R, Li E, Jaenisch R. Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA 1994; 91: 11797-11801.
55. Bouchard J, Momparler RL. Incorporation of 5-aza-2′-deoxycytidine-5′-triphosphate into DNA. Interactions with mammalian DNA polymerase alpha and DNA methylase. Mol Pharmacol 1983; 24: 109-114.
56. Santi DV, Garrett CE, Barr PJ. On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell 1983; 33: 9-10.
57. Lin KT, Momparler RL, Rivard GE. High-performance liquid chromatographic analysis of chemical stability of 5-aza-2′-deoxycytidine. J Pharm Sci 1981; 70: 1228-1232.
58. D'Incalci M, Covey JM, Zaharko DS, Kohn KW. DNA alkali-labile sites induced by incorporation of 5-aza-2′-deoxycytidine into DNA of mouse leukemia L1210 cells. Cancer Res 1985; 45: 3197-3202.
59. Bender CM, Pao MM, Jones PA. Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res 1998; 58: 95-101.
60. Attadia V. Effects of 5-aza-2′-deoxycytidine on differentiation and oncogene expression in the human monoblastic leukemia cell line U-937. Leukemia 1993; 7 (Suppl. 1): 9-16.
61. Momparler RL, Samson J, Momparler LF, Rivard GE. Cell cycle effects and cellular pharmacology of 5-aza-2′-deoxycytidine. Cancer Chemother Pharmacol 1984; 13: 191-194.
62. Crooke ST. Potential roles of antisense technology in cancer chemotherapy. Oncogene 2000; 19: 6651-6659.
63. MacLeod AR, Szyf M. Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem 1995; 270: 8037-8043.
64. Kantharidis P, El Osta A, deSilva M et al. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance. Clin Cancer Res 1997; 3: 2025-2032.
65. Counts JL, Goodman JI. Hypomethylation of DNA: an epigenetic mechanism involved in tumor promotion. Mol Carcinog 1994; 11: 185-188.
66. Carr BI, Rahbar S, Asmeron Y et al. Carcinogenicity and haemoglobin synthesis induction by cytidine analogues. Br J Cancer 1988; 57: 395-402.
67. Momparler RL, Goodman J. In vitro cytotoxic and biochemical effects of 5-aza-2′-deoxycytidine. Cancer Res 1977; 37: 1636-1639.
68. Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2′-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res 1983; 43: 3493-3496.
69. Momparler RL, Bouchard J, Samson J. Induction of differentiation and inhibition of DNA methylation in HL-60 myeloid leukemic cells by 5-aza-2′-deoxycytidine. Leuk Res 1985; 9: 1361-1366.
70. Pinto A, Attadia V, Fusco A et al. 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood 1984; 64: 922-929.
71. Momparler RL, Bouchard J, Onetto N, Rivard GE. 5-Aza-2′-deoxycytidine therapy in patients with acute leukemia inhibits DNA methylation. Leuk Res 1984; 8: 181-185.
72. Costello JF, Berger MS, Huang HS, Cavenee WK. Silencing of P16/ CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res 1996; 56: 2405-2410.
73. Merlo A, Herman JG, Mao L et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor P16/CDKN2/MTS1 in human cancers. Nature Med 1995; 1: 686-692.
74. Deng G, Chen A, Hong J et al. Methylation of CpG in a small region of the HMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res 1999; 59: 2029-2033.
75. van Groeningen CJ, Leyva A, O'Brien AM et al. Phase I and pharmacokinetic study of 5-aza-2′-deoxycytidine (NSC 127716) in cancer patients. Cancer Res 1986; 46: 4831-4836.
76. Abele R, Clavel M, Dodion P et al. The EORTC early clinical trials cooperative group experience with 5-aza-2′-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignant melanomas. Eur J Cancer Clin Oncol 1987; 23: 1921-1924.
77. Clavel M, Monfardini S, Fossa S et al. 5-Aza-2′-deoxycytidine (NSC 127716) in non-seminomatous testicular cancer. Phase II from the EORTC Early Clinical Trials Cooperative Group and Genito-Urinary Group. Ann Oncol 1992; 3: 399-400.
78. Sessa C, ten Bokkel Huinink W, Stoter G et al. Phase II study of 5-aza-2′-deoxycytidine in advanced ovarian carcinoma. The EORTC Early Clinical Trials Group. Eur J Cancer 1990; 26: 137-138.
79. Thibault A, Figg WD, Bergan RC et al. A phase II study of 5-aza-2′-deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer. Tumori 1998; 84: 87-89.
80. Vermorken JB, Tumolo S, Roozendaal KJ et al. 5-Aza-2′-deoxycytidine in advanced or recurrent cancer of the uterine cervix. Eur J Cancer 1991; 27: 216-217.
81. Momparler RL, Bouffard DY, Momparler LF et al. Pilot phase I-II study on 5-aza-2′-deoxycytidine (decitabine) in patients with metastatic lung cancer. Anticancer Drugs 1997; 8: 358-368.
82. Schwartsmann G, Schunemann H, Gorini CN 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 2000; 18: 83-91.
83. Rivard GE, Momparler RL, Demers J et al. Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res 1981; 5: 453-462.
84. Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther 1985; 30: 277-286.
85. Petti MC, Mandelli F, Zagonel V et al. Pilot study of 5-aza-2′-deoxycytidine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia 1993; 7 (Suppl. 1): 36-41.
86. Kantarjian HM, O'Brien SM, Estey E et al. Decitabine studies in chronic and acute myelogenous leukemia. Leukemia 1997; 11 (Suppl. 1): S35-S36.
87. Kantarjian HM, O'Brien SM, Keating M et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 1997; 11: 1617-1620.
88. Sacchi S, Kantarjian HM, O'Brien S et al. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 1999; 86: 2632-2641.
89. Schwartsmann G, Fernandes MS, Schaan MD et al. Decitabine (5-aza-2′-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 1997; 11 (Suppl. 1): S28-S31.
90. Richel DJ, Colly LP, Kluin-Nelemans JC, Willemze R. The anti-leukaemic activity of 5-aza-2′-deoxycytidine (aza-DC) in patients with relapsed and resistant leukaemia. Br J Cancer 1991; 64: 144-148.
91. Willemze R, Suciu S, Archimbaud E et al. A randomized phase II study on the effects of 5-aza-2′-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group Phase II Study (06893). Leukemia 1997; 11 (Suppl. 1): S24-S27.
92. 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: 237-245.
93. Israili ZH, Vogler WR, Mingioli ES et al. The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion. Cancer Res 1976; 36: 1453-1461.
94. Li LH, Olin EJ, Buskirk HH, Reineke LM. Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 1970; 30: 2760-2769.
95. Sorm F, Vesely J. Effect of 5-aza-2′-deoxycytidine against leukemic and hemopoietic tissues in AKR mice. Neoplasma 1968; 15: 339-343.
96. Driscoll JS, Johns DG, Plowman J. Comparison of the activity of arabinosyl-5-azacytosine, arabinosyl cytosine, and 5-azacytidine against intracerebrally implanted L1210 leukemia. Invest New Drugs 1985; 3: 331-334.
97. Christman JK, Mendelsohn N, Herzog D, Schneiderman N. Effect of 5-azacytidine on differentiation and DNA methylation in human promyelocytic leukemia cells (HL-60). Cancer Res 1983; 43: 763-769.
98. Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2′-deoxycytidine. J Biol Chem 1982; 257: 2041-2048.
99. + thalassemia. N Engl J Med 1982; 307: 1469-1475.
100. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA 1982; 79: 4428-4431.
101. Troetel WM, Weiss AJ, Stambaugh JE. Absorption, distribution, and excretion of 5-azacytidine (NSC-1028116) in man. Cancer Chemother Rep 1972; 56: 405-411.
102. Weiss AJ, Stambaugh JF, Mastrangelo MJ. Phase I study of 5-azacytidine (NSC-102816). Cancer Chemother Rep 1972; 56: 413-419.
103. Vogler WR, Arkun S, Velez-Garcia E. Phase I study of twice weekly 5-azacytidine (NSC-102816). Cancer Chemother Rep 1974; 58: 895-899.
104. Lomen PL, Baker LH, Neil GL, Samson MK. Phase I study of 5-azacytidine (NSC-102816) using 24-hour continuous infusion for 5 days. Cancer Chemother Rep 1975; 59: 1123-1126.
105. Vogler WR, Miller DS, Keller JW. 5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. Blood 1976; 48: 331-337.
106. Bellet RE, Mastrangelo MJ, Engstrom PF et al. Clinical trial with subcutaneously administered 5-azacytidine (NSC-102816). Cancer Chemother Rep 1974; 58: 217-222.
107. Weiss AJ, Metter GE, Nealon TF et al. Phase II study of 5-azacytidine in solid tumors. Cancer Treat Rep 1977; 61: 55-58.
108. Quagliana JM, O'Bryan RM, Baker L et al. Phase II study of 5-azacytidine in solid tumors. Cancer Treat Rep 1977; 61: 51-54.
109. Hrodek O, Vesely J. 5-Azacytidine in childhood leukemia. Neoplasma 1971; 18: 493-503.
110. Weinstein HJ, Mayer RJ, Rosenthal DS et al. Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 1983; 62: 315-319.
111. Baehner RL, Bernstein ID, Sather H et al. Improved remission induction rate with D-ZAPO but unimproved remission duration with addition of immunotherapy to chemotherapy in previously untreated children with ANLL. Med Pediatr Oncol 1979; 7: 127-139.
112. Baehner RL, Bernstein ID, Sather H et al. Contrasting benefits of two maintenance programs following identical induction in children with acute nonlymphocytic leukemia: a report from the Children's Cancer Study Group. Cancer Treat Rep 1984; 68: 1269-1272.
113. Karon M, Sieger L, Leimbrock S et al. 5-Azacytidine: a new active agent for the treatment of acute leukemia. Blood 1973; 42: 359-365.
114. Nitschke R, Land V, Steuber CP, Ragab AH. 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 1981; 3: 307-309.
115. Look AT, Dahl GV, Kalwinsky D et al. Effective remission induction of refractory childhood acute nonlymphocytic leukemia by VP-16-213 plus azacitidine. Cancer Treat Rep 1981; 65: 995-999.
116. Hakami N, Look AT, Steuber PC et al. Combined etoposide and 5-azacitidine in children and adolescents with refractory or relapsed acute nonlymphocytic leukemia: a Pediatric Oncology Group study. J Clin Oncol 1987; 5: 1022-1025.
117. Steuber CP, Holbrook T, Camitta B et al. Toxicity trials of amsacrine (AMSA) and etoposide plus or minus azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL): a pilot study. Invest New Drugs 1991; 9: 181-184.
118. Steuber CP, Krischer J, Holbrook T et al. Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group Randomized Phase II study. J Clin Oncol 1996; 14: 1521-1525.
119. Cassileth PA, Petrillo MH, Cooper RA, Katz ME. Feasibility and efficacy of 5-azacytidine used early in the therapy of adult acute nonlymphocytic leukemia: an ECOG pilot study. Cancer Clin Trials 1979; 2: 339-343.
120. Vogler WR, Winton EF, Gordon DS et al. A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood 1984; 63: 1039-1045.
121. McCredie KB, Bodey GP, Burgess MA et al. Treatment of acute leukemia with 5-azacytidine (NSC-102816). Cancer Chemother Rep 1973; 57: 319-323.
122. Levi JA, Wiernik PH. A comparative clinical trial of 5-azacytidine and guanazole in previously treated adults with acute nonlymphocytic leukemia. Cancer 1976; 38: 36-41.
123. Saiki JH, McCredie KB, Vietti TJ et al. 5-Azacytidine in acute leukemia. Cancer 1978; 42: 2111-2114.
124. Saiki JH, Bodey GP, Hewlett JS et al. Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia: a Southwest Oncology Group study. Cancer 1981; 47: 1739-1742.
125. Kahn SB, Sklaroff R, Lebedda J et al. 4′-(9-Acridinylamino)methane-sulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA) in the treatment of relapsed adult acute leukemia. Am J Clin Oncol 1983; 6: 493-502.
126. Worsley AM, Catovsky D, Goldman JM, Galton DA. New combination chemotherapy for relapsed acute myeloid leukaemia. Lancet 1984; 1: 1232.
127. Winton EF, Hearn EB, Martelo O et al. Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: a phase I-II trial of the Southeastern Cancer Study Group. Cancer Treat Rep 1985; 69: 807-811.
128. Omura GA. Combination therapy with 5-azacytidine plus β-2′-deoxythioguanosine in adult acute leukemia. Cancer Treat Rep 1977; 61: 915-917.
129. Omura GA, Vogler WR, Bartolucci A et al. Treatment of refractory adult acute leukemia with 5-azacytidine plus β-2′-deoxythioguanosine. Cancer Treat Rep 1979; 63: 209-210.
130. Peterson BA, Bloomfield CD, Gottlieb AJ et al. 5-Azactidine and zorubicin for patients with previously treated acute nonlymphocytic leukemia: a Cancer and Leukemia Group B Pilot study. Cancer Treat Rep 1982; 66: 563-566.
131. Goldberg J, Gryn J, Raza A et al. Mitoxantrone and 5-azacytidine for refractory/relapsed ANLL or CML in blast crisis: a Leukemia Intergroup study. Am J Hematol 1993; 43: 286-290.
132. Martelo OJ, Broun GO Jr, Petruska PJ. Phase I study of pyrazofurin and 5-azacytidine in refractory adult acute leukemia. Cancer Treat Rep 1981; 65: 237-239.
133. Van Echo DA, Chiuten DF, Markus S, Wiernik PH. A clinical trial of pyrazofurin in combination with 5-azacytidine in acute adult non-lymphocytic leukemia. Cancer Clin Trials 1981; 4: 129-133.
134. Chahinian AP, Ohnuma T, Greenfield DS, Holland JF. Sequential combination of pyrazofurin and 5-azacytidine in patients with acute myelocytic leukemia and carcinoma. Oncology 1981; 38: 7-12.
135. Kritz AD, Raptis G, Menendez-Botet C et al. Pilot study of 5-azacytidine (5-AZA) and carboplatin (CBDCA) in patients with relapsed/refractory leukemia. Am J Hematol 1996; 51: 117-121.
136. Levi JA, Wiernik PH. Combination therapy with 5-azacytidine (NSC-102816) and methyl-GAG (NSC-32946) in previously treated adults with acute nonlymphocytic leukemia. Cancer Chemother Rep 1975; 59: 1043-1045.
137. Van Echo DA, Lichtenfeld KM, Wiernik PH. Vinblastine, 5-azacytidine, and VP-16-213 therapy for previously treated patients with acute nonlymphocytic leukemia. Cancer Treat Rep 1977; 61: 1599-1602.
138. Winton EF, Miller D, Vogler WR. Intensive chemotherapy with daunorubicin, 5-azacytidine, 6-thioguanine, and cytarabine (DATA) for the blastic transformation of chronic granulocytic leukemia. Cancer Treat Rep 1981; 65: 389-392.
139. Schiffer CA, DeBellis R, Kasdorf H, Wiernik PH. Treatment of the blast crisis of chronic myelogenous leukemia with 5-azacitidine and VP-16-213. Cancer Treat Rep 1982; 66: 267-271.
140. Schiffer CA, Anderson K, Coleman M, Cuttner J. Therapy for chronic myelogenous leukemia in blast crisis with etoposide and 5-azacitidine administered by continuous infusion: a Cancer and Leukemia Group B study. Cancer Treat Rep 1985; 69: 1027-1028.
141. Dutcher JP, Eudey L, Wiernik PH et al. Phase II study of mitoxantrone and 5-azacytidine for accelerated and blast crisis of chronic myelogenous leukemia: a Eastern Cooperative Oncology Group study. Leukemia 1992; 6: 770-775.
142. National Institutes of Health. Clinical Trials [on-line]. http://clinicaltrials.gov/ct/gui/c/w2r/action/SearchAction?JServSession Idzone=fmrwwrh721&Term=azacitidine (October 2002, date last accessed).
143. Beisler JA, Abbasi MM, Driscoll JS. Synthesis and antitumor activity of 5-azacytosine arabinoside. J Med Chem 1979; 22: 1230-1234.
144. Ahluwalia GS, Cohen MB, Kang GJ et al. Arabinosyl-5-azacytosine: mechanisms of native and acquired resistance. Cancer Res 1986; 46: 4479-4485.
145. Grem JL, Shoemaker DD, Hoth DF et al. Arabinosyl-5-azacytosine: a novel nucleoside entering clinical trials. Invest New Drugs 1987; 5: 315-328.
146. Vesely J, Piskala A. Mechanism of action of 1-β-D-arabinofuranosyl-5-azacytosine and its effects in L1210 mouse leukemia cells. Neoplasma 1986; 33: 3-10.
147. Bernstein ML, Whitehead VM, Grier H et al. A phase I trial of fazarabine in refractory pediatric solid tumors. A Pediatric Oncology Group study. Invest New Drugs 1993; 11: 309-312.
148. Heideman RL, Gillespie A, Ford H et al. Phase I trial and pharmacokinetic evaluation of fazarabine in children. Cancer Res 1989; 49: 5213-5216.
149. Bailey H, Tutsch KD, Arzoomanian RZ et al. Phase I clinical trial of fazarabine as a twenty-four-hour continuous infusion. Cancer Res 1991; 51: 1105-1108.
150. Goldberg RM, Reid JM, Ames MM et al. Phase I and pharmacological trial of fazarabine (Ara-AC) with granulocyte colony-stimulating factor. Clin Cancer Res 1997; 3: 2363-2370.
151. Amato R, Ho D, Schmidt S et al. Phase I trial of a 72-h continuous-infusion schedule of fazarabine. Cancer Chemother Pharmacol 1992; 30: 321-324.
152. Surbone A, Ford H Jr, Kelley JA et al. Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). Cancer Res 1990; 50: 1220-1225.
153. Wilhelm M, O'Brien S, Rios MB et al. Phase I study of arabinosyl-5-azacytidine (fazarabine) in adult acute leukemia and chronic myelogenous leukemia in blastic phase. Leuk Lymphoma 1999; 34: 511-518.
154. Selby GB, Upchurch C, Townsend J, Eyre HJ. A phase II evaluation of fazarabine in high-grade gliomas: a Southwest Oncology Group study. Cancer Chemother Pharmacol 1994; 34: 179-180.
155. Kuebler JP, Metch B, Schuller DE et al. Phase II study of fazarabine in advanced head and neck cancer. A Southwest Oncology Group study. Invest New Drugs 1991; 9: 373-374.
156. Manetta A, Blessing JA, Mann WJ, Smith DM. A phase II study of fazarabine (NSC 281272) in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Am J Clin Oncol 1995; 18: 439-440.
157. Manetta A, Blessing JA, Look KY. A phase II study of fazarabine in patients with advanced ovarian cancer. A Gynecologic Oncology Group study. Am J Clin Oncol 1995; 18: 156-157.
158. Williamson SK, Crowley JJ, Livingston RB et al. Phase II trial and cost analysis of fazarabine in advanced non-small cell carcinoma of the lung: a Southwest Oncology Group study. Invest New Drugs 1995; 13: 67-71.
159. Walters RS, Theriault RL, Holmes FA et al. Phase II trial of fazarabine (ARA-AC, arabinosyl-5-azacytosine) in metastatic breast cancer. Invest New Drugs 1992; 10: 43-44.
160. Ben Baruch N, Denicoff AM, Goldspiel BR et al. Phase II study of fazarabine (NSC 281272) in patients with metastatic colon cancer. Invest New, Drugs 1993; 11: 71-74.
161. Hubbard KP, Daugherty K, Ajani JA et al. Phase II trial of fazarabine in advanced colorectal carcinoma. Invest New Drugs 1992; 10: 39-42.
162. Casper ES, Schwartz GK, Kelsen DP. Phase II trial of fazarabine (arabinofuranosyl-5-azacytidine) in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 1992; 10: 205-209.
163. Beisler JA, Abbasi MM, Kelley JA, Driscoll JS. Synthesis and antitumor activity of dihydro-5-azacytidine, a hydrolytically stable analogue of 5-azacytidine. J Med Chem 1977; 20: 806-812.
164. Glazer RI, Hartman KD. The comparative effects of 5-azacytidine and dihydro-5-azacytidine on 4S and 5S nuclear RNA. Mol Pharmacol 1980; 17: 250-255.
165. Traganos F, Staiano-Coico L, Darzynkiewicz Z, Melamed MR. Effects of dihydro-5-azacytidine on cell survival and cell cycle progression of cultured mammalian cells. Cancer Res 1981; 41: 780-789.
166. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980; 20: 85-93.
167. Curt GA, Kelley JA, Fine RL et al. A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880). Cancer Res 1985; 45: 3359-3363.
168. Holoye PY, Dhingra HM, Umsawasdi T et al. Phase II study of 5,6-dihydro-5-azacytidine in extensive, untreated non-small cell lung cancer. Cancer Treat Rep 1987; 71: 859-860.
169. Creagan ET, Schaid DJ, Hartmann LC, Loprinzi CL. A phase II study of 5,6-dihydro-5-azacytidine hydrochloride in disseminated malignant melanoma. Am J Clin Oncol 1993; 16: 243-244.
170. Dhingra HM, Murphy WK, Winn RJ et al. Phase II trial of 5,6-dihydro-5-azacytidine in pleural malignant mesothelioma. Invest New Drugs 1991; 9: 69-72.
171. Vogelzang NJ, Herndon JE, Cirrincione C et al. Dihydro-5-aza-cytidine in malignant mesothelioma. A phase II trial demonstrating activity accompanied by cardiac toxicity. Cancer and Leukemia Group B. Cancer 1997; 79: 2237-2242.
172. Samuels BL, Herndon JE, Harmon DC et al. Dihydro-5-azacytidine and cisplatin in the treatment of malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Cancer 1998; 82: 1578-1584.
173. Beaulieu N, Fournel M, Macleod A. Antitumor activity of MG98, an antisense oligonucleotide targeting DNA methyltransferase-1 (DNMT1). Clin Cancer Res 2001; 7 (Suppl.): 3800S (Abstr 728).
174. Beaulieu N, Fournel M, Siders B, Macleod A. Synergistic antitumor activity of MG98 (antisense oligonucleotide targeting DNMT1) in combination with 5-aza-deoxycytosine. Clin Cancer Res 2001; 7 (Suppl.): 3800S-3801S (Abstr 731).
175. Besterman J, Younan J, Marquis J. MG98 (DNMT1-directed antisense oligodeoxynucleotide): toxicity studies in Cynomolgus monkeys. Clin Cancer Res 2001; 11 (Suppl.): 3707S (Abstr 269).
176. Davis AJ, Moore MJ, Gelmon KA et al. Phase 1 and pharmacodynamic study of human DNA methyltransferase (MeTase) antisense oligodeoxynucleotide (ODN), MG98, administered as 21-day infusion q4 weekly. Clin Cancer Res 2000; 6 (Suppl.): 4517S (Abstr 257).
177. Donehower R, Stewart D, Eisenhauer E et al. A phase I and pharmacokinetic (PK) study of MG98, a human DNA methyltransferase (DNMT) mRNA inhibitor, given as a 2-hour twice weekly (BIW) infusion 3 out of every 4 weeks. Clin Cancer Res 2001; 11 (Suppl.): 3680S (Abstr 133).
178. Buyse M, Thirion P, Carlson RW et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 2000; 356: 373-378.
179. Graf W, Pahlman L, Bergstrom R, Glimelius B. The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 1994; 70: 559-563.
180. Paesmans M, Sculier JP, Libert P et al. Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party. Eur J Cancer 1997; 33: 2326-2332.
181. Markman M. Why does a higher response rate to chemotherapy correlate poorly with improved survival? J Cancer Res Clin Oncol 1993; 119: 700-701.
182. Gelmon KA, Eisenhauer EA, Harris AL et al. Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst 1999; 91: 1281-1287.
183. Rapp E, Pater JL, Willan A et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer - report of a Canadian Multicenter Randomized Trial. J Clin Oncol 1988; 6: 633-641.
184. Murray N, Coppin C, Coldman A et al. Drug delivery analysis of the Canadian Multicenter Trial in Non-Small-Cell Lung Cancer. J Clin Oncol 1994; 12: 2333-2339.
185. Cesano A, Lane SR, Poulin R et al. Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small-cell-lung cancer and ovarian cancer patients. Int J Oncol 1999; 15: 1233-1238.
186. Howell A, Mackintosh J, Jones M et al. The definition of the 'no change' category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast. Eur J Cancer Clin Oncol 1988; 24: 1567-1572.
187. Eisenhauer EA. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. The Michel Clavel Lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16-19 June 1998. Ann Oncol 1998; 9: 1047-1052.
188. Yoshida M, Furumai R, Nishiyama M et al. Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol 2001; 48 (Suppl. 1): S20-S26.
189. Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of 5-azacytidine (NSC-102816) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972; 56: 649-652.
190. Cunningham TJ, Nemoto T, Rosner D et al. Comparison of 5-azacytidine (NSC-102816) with CCNU (NSC-79037) in the treatment of patients with breast cancer and evaluation of the subsequent use of cyclophosphamide (NSC-26271). Cancer Chemother Rep 1974; 58: 677-681.
191. Srinivasan U, Reaman GH, Poplack DG et al. Phase II study of 5-azacytidine in sarcomas of bone. Am J Clin Oncol 1982; 5: 411-415.
192. Velez-Garcia E, Vogler WR, Bartolucci AA, Arkun, SN. Twice weekly 5-azacytidine infusion in dissmeinated metastatic cancer: a phase II study. Cancer Treat Rep 1977; 61: 1675-1677.
193. Roth BJ, Elson P, Sledge GW Jr et al. 5-Azacytidine (NSC 102816) in refractory germ cell tumors. A phase II trial of the Eastern Cooperative Oncology Group. Invest New Drugs 1993; 11: 201-202.