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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1635-1640. Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-03-0687. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0687v1 103/5/1635    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Issa, J.-P. J. Articles by Kantarjian, H. M. Search for Related Content PubMed PubMed Citation Articles by Issa, J.-P. J. Articles by Kantarjian, H. M. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies Jean-Pierre J. Issa, Guillermo Garcia-Manero, Francis J. Giles, Rajan Mannari, Deborah Thomas, Stefan Faderl, Emel Bayar, John Lyons, Craig S. Rosenfeld, Jorge Cortes, and Hagop M. Kantarjian From the Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX; and SuperGen Inc, Dublin, CA. Decitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Nojima, R. Maruyama, H. Yasui, H. Suzuki, Y. Maruyama, I. Tarasawa, Y. Sasaki, H. Asaoku, H. Sakai, T. Hayashi, et al. Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma Clin. Cancer Res., July 1, 2009; 15(13): 4356 - 4364. [Abstract] [Full Text] [PDF] J.-P. J. Issa and H. M. Kantarjian Targeting DNA Methylation Clin. Cancer Res., June 15, 2009; 15(12): 3938 - 3946. [Abstract] [Full Text] [PDF] D. J. Stewart, J.-P. Issa, R. Kurzrock, M. I. Nunez, J. Jelinek, D. Hong, Y. Oki, Z. Guo, S. Gupta, and I. I. 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CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha Blood, November 15, 2007; 110(10): 3695 - 3705. [Abstract] [Full Text] [PDF] E. R. Plimack, D. J. Stewart, and J.-P. J. Issa Combining Epigenetic and Cytotoxic Therapy in the Treatment of Solid Tumors J. Clin. Oncol., October 10, 2007; 25(29): 4519 - 4521. [Full Text] [PDF] K. Appleton, H. J. Mackay, I. Judson, J. A. Plumb, C. McCormick, G. Strathdee, C. Lee, S. Barrett, S. Reade, D. Jadayel, et al. Phase I and Pharmacodynamic Trial of the DNA Methyltransferase Inhibitor Decitabine and Carboplatin in Solid Tumors J. Clin. Oncol., October 10, 2007; 25(29): 4603 - 4609. [Abstract] [Full Text] [PDF] W. Blum, R. B. Klisovic, B. Hackanson, Z. Liu, S. Liu, H. Devine, T. Vukosavljevic, L. Huynh, G. Lozanski, C. Kefauver, et al. Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia J. Clin. Oncol., September 1, 2007; 25(25): 3884 - 3891. [Abstract] [Full Text] [PDF] C. B. Yoo, S. Jeong, G. Egger, G. Liang, P. Phiasivongsa, C. Tang, S. Redkar, and P. A. Jones Delivery of 5-Aza-2'-Deoxycytidine to Cells Using Oligodeoxynucleotides Cancer Res., July 1, 2007; 67(13): 6400 - 6408. [Abstract] [Full Text] [PDF] E. Fonsatti, H. J.M. Nicolay, L. Sigalotti, L. Calabro, L. Pezzani, F. Colizzi, M. Altomonte, M. Guidoboni, F. M. Marincola, and M. Maio Functional Up-regulation of Human Leukocyte Antigen Class I Antigens Expression by 5-aza-2'-deoxycytidine in Cutaneous Melanoma: Immunotherapeutic Implications Clin. Cancer Res., June 1, 2007; 13(11): 3333 - 3338. [Abstract] [Full Text] [PDF] M. Ishiguro, S. Iida, H. Uetake, S. Morita, H. Makino, K. Kato, Y. Takagi, M. Enomoto, and K. Sugihara Effect of Combined Therapy With Low-Dose 5-Aza-2'-Deoxycytidine and Irinotecan on Colon Cancer Cell Line HCT-15 Ann. Surg. Oncol., May 1, 2007; 14(5): 1752 - 1762. [Abstract] [Full Text] [PDF] C. 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Dai Frequent Epigenetic Inactivation of Spleen Tyrosine Kinase Gene in Human Hepatocellular Carcinoma. Clin. Cancer Res., November 15, 2006; 12(22): 6687 - 6695. [Abstract] [Full Text] [PDF] G. Garcia-Manero, H. M. Kantarjian, B. Sanchez-Gonzalez, H. Yang, G. Rosner, S. Verstovsek, M. Rytting, W. G. Wierda, F. Ravandi, C. Koller, et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia Blood, November 15, 2006; 108(10): 3271 - 3279. [Abstract] [Full Text] [PDF] V. Davalos, H. Dopeso, J. Castano, A. J. Wilson, F. Vilardell, J. Romero-Gimenez, E. Espin, M. Armengol, G. Capella, J. M. Mariadason, et al. EPHB4 and Survival of Colorectal Cancer Patients. Cancer Res., September 15, 2006; 66(18): 8943 - 8948. [Abstract] [Full Text] [PDF] S. D. Gore, S. Baylin, E. Sugar, H. Carraway, C. B. Miller, M. Carducci, M. Grever, O. Galm, T. Dauses, J. E. Karp, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res., June 15, 2006; 66(12): 6361 - 6369. [Abstract] [Full Text] [PDF] A. S. Yang, K. D. Doshi, S.-W. Choi, J. B. Mason, R. K. Mannari, V. Gharybian, R. Luna, A. Rashid, L. Shen, M. R.H. Estecio, et al. DNA Methylation Changes after 5-Aza-2'-Deoxycytidine Therapy in Patients with Leukemia. Cancer Res., May 15, 2006; 66(10): 5495 - 5503. [Abstract] [Full Text] [PDF] E. Yuan, F. Haghighi, S. White, R. Costa, J. McMinn, K. Chun, M. Minden, and B. Tycko A single nucleotide polymorphism chip-based method for combined genetic and epigenetic profiling: validation in decitabine therapy and tumor/normal comparisons. Cancer Res., April 1, 2006; 66(7): 3443 - 3451. [Abstract] [Full Text] [PDF] J.-P. Issa Measuring the Impact of Epigenetic Therapy on DNA Methylation and Gene Expression Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 197 - 198. [Full Text] [PDF] C. Stresemann, B. Brueckner, T. Musch, H. Stopper, and F. Lyko Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res., March 1, 2006; 66(5): 2794 - 2800. [Abstract] [Full Text] [PDF] R. M. Brena, H. Auer, K. Kornacker, B. Hackanson, A. Raval, J. C. Byrd, and C. Plass Accurate quantification of DNA methylation using combined bisulfite restriction analysis coupled with the Agilent 2100 Bioanalyzer platform Nucleic Acids Res., February 7, 2006; 34(3): e17 - e17. [Abstract] [Full Text] [PDF] E. J. Jabbour, E. Estey, and H. M. Kantarjian Adult Acute Myeloid Leukemia Mayo Clin. Proc., February 1, 2006; 81(2): 247 - 260. [Abstract] [Full Text] [PDF] M. Herranz, J. Martin-Caballero, M. F. Fraga, J. Ruiz-Cabello, J. M. Flores, M. Desco, V. Marquez, and M. Esteller The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma Blood, February 1, 2006; 107(3): 1174 - 1177. [Abstract] [Full Text] [PDF] M. T. McCabe, J. A. Low, S. Daignault, M. J. Imperiale, K. J. Wojno, and M. L. Day Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer Cancer Res., January 1, 2006; 66(1): 385 - 392. [Abstract] [Full Text] [PDF] C. A. Schiffer Clinical Issues in the Management of Patients with Myelodysplasia Hematology, January 1, 2006; 2006(1): 205 - 210. [Abstract] [Full Text] [PDF] A. Eramo, R. Pallini, F. Lotti, G. Sette, M. Patti, M. Bartucci, L. Ricci-Vitiani, M. Signore, G. Stassi, L. M. Larocca, et al. Inhibition of DNA Methylation Sensitizes Glioblastoma for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Destruction Cancer Res., December 15, 2005; 65(24): 11469 - 11477. [Abstract] [Full Text] [PDF] C. A. Ortmann, A. Burchert, K. Holzle, A. Nitsche, B. Wittig, A. Neubauer, and M. Schmidt Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region Nucleic Acids Res., December 7, 2005; 33(21): 6895 - 6905. [Abstract] [Full Text] [PDF] L. C. Hsi, X. Xi, Y. Wu, and S. M. Lippman The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells Mol. Cancer Ther., November 1, 2005; 4(11): 1740 - 1746. [Abstract] [Full Text] [PDF] F. Lyko and R. Brown DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies J Natl Cancer Inst, October 19, 2005; 97(20): 1498 - 1506. [Abstract] [Full Text] [PDF] C. Balch, P. Yan, T. Craft, S. Young, D. G. Skalnik, T. H-M. Huang, and K. P. Nephew Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer Mol. Cancer Ther., October 1, 2005; 4(10): 1505 - 1514. [Abstract] [Full Text] [PDF] J. R Kuykendall 5-Azacytidine and Decitabine Monotherapies of Myelodysplastic Disorders Ann. Pharmacother., October 1, 2005; 39(10): 1700 - 1708. [Abstract] [Full Text] [PDF] C. Mund, B. Hackanson, C. Stresemann, M. Lubbert, and F. Lyko Characterization of DNA Demethylation Effects Induced by 5-Aza-2'-Deoxycytidine in Patients with Myelodysplastic Syndrome Cancer Res., August 15, 2005; 65(16): 7086 - 7090. [Abstract] [Full Text] [PDF] W. E. Samlowski, S. A. Leachman, M. Wade, P. Cassidy, P. Porter-Gill, L. Busby, R. Wheeler, K. Boucher, F. Fitzpatrick, D. A. Jones, et al. Evaluation of a 7-Day Continuous Intravenous Infusion of Decitabine: Inhibition of Promoter-Specific and Global Genomic DNA Methylation J. Clin. Oncol., June 10, 2005; 23(17): 3897 - 3905. [Abstract] [Full Text] [PDF] J.-P. J. Issa, V. Gharibyan, J. Cortes, J. Jelinek, G. Morris, S. Verstovsek, M. Talpaz, G. Garcia-Manero, and H. M. Kantarjian Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate J. Clin. Oncol., June 10, 2005; 23(17): 3948 - 3956. [Abstract] [Full Text] [PDF] K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF] R. van Doorn, W. H. Zoutman, R. Dijkman, R. X. de Menezes, S. Commandeur, A. A. Mulder, P. A. van der Velden, M. H. Vermeer, R. Willemze, P. S. Yan, et al. Epigenetic Profiling of Cutaneous T-Cell Lymphoma: Promoter Hypermethylation of Multiple Tumor Suppressor Genes Including BCL7a, PTPRG, and p73 J. Clin. Oncol., June 10, 2005; 23(17): 3886 - 3896. [Abstract] [Full Text] [PDF] K. Miyamoto and T. Ushijima Diagnostic and Therapeutic Applications of Epigenetics Jpn. J. Clin. Oncol., June 1, 2005; 35(6): 293 - 301. [Abstract] [Full Text] [PDF] P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF] C. B. Yoo and P. A. Jones DNA Methyltransferase Inhibitors in Cancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 333 - 337. [Full Text] [PDF] G. Garcia-Manero, H. Kantarjian, B. Sanchez-Gonzalez, S. Faderl, S. Verstovsek, F. Ravandi, M. Ryttling, J. Cortes, W. Wierda, K. Hoshino, et al. Results of a Phase I/II Study of the Combination of 5-aza-2'-Deoxycytidine (DAC) and Valproic Acid (VPA) in Patients (pts) with Leukemia. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 263 - 263. [Abstract] Y. Kondo, L. Shen, P. S. Yan, T. H.-M. Huang, and J.-P. J. Issa Chromatin immunoprecipitation microarrays for identification of genes silenced by histone H3 lysine 9 methylation PNAS, May 11, 2004; 101(19): 7398 - 7403. [Abstract] [Full Text] [PDF] J. E. Dowell and J. D. Minna Cancer Chemotherapy Targeted at Reactivating the Expression of Epigenetically Inactivated Genes J. Clin. Oncol., April 15, 2004; 22(8): 1353 - 1355. [Full Text] [PDF] A. F. List, J. Vardiman, J.-P. J. Issa, and T. M. DeWitte Myelodysplastic Syndromes Hematology, January 1, 2004; 2004(1): 297 - 317. [Abstract] [Full Text] [PDF] G. C. Bagby, J. M. Lipton, E. M. Sloand, and C. A. Schiffer Marrow Failure Hematology, January 1, 2004; 2004(1): 318 - 336. [Abstract] [Full Text] [PDF]

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