Abstract
Decitabine (5-aza-2p-deoxycytidine) is a hypomethylation agent with a double-action mechanism, these are the reactivation of silenced genes; exhibiting differentiation at low doses and showing cytotoxicity at high doses. Decitabine was used as a classic anticancer drug in the original studies in the 1980s, 1500 to 2500 mg/m2 per cycle was the maximum clinically tolerated dose. The dosage was reassessed after a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylation) therapy was obtained, in about 1/20th of the previous doses (i.e., 'optimal biological' doses modulating hypomethylation). It has been found that decitabine (100 to 150 mg / m2 per cycle) can be used in patients with myelodysplastic syndromes (MDS) and other myeloid tumors, with manageable side effects. Combination therapies that amplify the epigenetic effect of decitabine will most likely improve the patient responses and allow it to be used in the treatment of other malignancies.
References
Nie J, Liu L, Li X, Han W. Decitabine, a New Star in Epigenetic Therapy: The Clinical Application and Biological Mechanism in Solid Tumors. Cancer Lett. 2014 Nov 1; 354(1):12-20. https://doi.org/10.1016/j.canlet.2014.08.010
Oki Y, Aoki E, Issa JP. Decitabine-bedside to bench. Crit Rev Oncol Hematol. 2007 Feb; 61(2):140-52. https://doi.org/10.1016/j.critrevonc.2006.07.010
Sorm F, Vesely J. Effect of 5-aza-2′-deoxycytidine against leukemic and hemopoietic tissues in AKR mice. Neoplasma. 1968; 15(4):339–343.
Momparler RL. Pharmacology of 5-Aza-2′-deoxycytidine (decitabine). Semin Hematol. 2005 Jul; 42(3 Suppl 2):9-16. https://doi.org/10.1053/j.seminhematol.2005.05.002
Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980 May; 20(1):85–93. https://doi.org/10.1016/0092-8674(80)90237-8
Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther. 1985; 30(3):277–286. https://doi.org/10.1016/0163-7258(85)90052-x
Rivard GE, Momparler Rl, Demers J, Benoit P, Raymond R, Lin K, et al. Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res. 1981; 5(6):453–462. https://doi.org/10.1016/0145-2126(81)90116-8
van Groeningen CJ, Leyva A, O’Brien AM, Gall HE, Pinedo HM. Phase I and pharmacokinetic study of 5-aza-2′-deoxycytidine (NSC 127716) in cancer patients. Cancer Res. 1986 Sep; 46(9):4831-6.
Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther. 1985; 30(3):277–286. https://doi.org/10.1016/0163-7258(85)90052-x
Rivard GE, Momparler Rl, Demers J, Benoit P, Raymond R, Lin K, et al. Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res. 1981; 5(6):453-62. https://doi.org/10.1016/0145-2126(81)90116-8
Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, et al. 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 Mar; 18(5):956–962. https://doi.org/10.1200/jco.2000.18.5.956
Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H. Evolution of Decitabine Development: accomplishments, Ongoing Investigations, and Future Strategies. Cancer. 2008 Jun;112(11):2341-51. https://doi.org/10.1002/cncr.23463
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006 Apr 15; 106(8):1794–803. https://doi.org/10.1002/cncr.21792
Cashen A, Schiller GJ, Larsen JS, Cullen MT, DiPersio JF. Phase II study of low-dose decitabine for the front-line treatment of older patients with acute myeloid leukemia (AML). Blood. 2006 Nov; 108(11):561. https://doi.org/10.1182/blood.V108.11.1984.1984
Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005 Jun 10; 23(17):3948–3956. https://doi.org/10.1200/jco.2005.11.981
Matei DE, Nephew KP. Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncol. 2010 Feb;116(2):195–201. https://doi.org/10.1016/j.ygyno.2009.09.043
Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, et al. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012 May 1; 72(9); 2197-205. https://doi.org/10.1158/0008-5472.can-11-3909
Garrido-Laguna I, McGregor KA, Wade M, Weis J, Gilcrease W, Burr L, et al. A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer. Invest New Drugs 2013 Oct; 31(5):1257–1264. https://doi.org/10.1007/s10637-013-9947-6
Chu BF, Karpenko MJ, Liu Z, Aimiuwu J, Villalona-Calero MA, Chan KK, et al. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer, Cancer Chemother Pharmacol. 2013 Jan;71 (1):115-21. https://doi.org/10.1007/s00280-012-1986-8
Issa JP. Decitabine. Curr Opin Oncol. 2003 Nov; 15(6): 446-51. https://doi.org/10.1097/00001622-200311000-00007
Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-Aza-2′-deoxycytidine. Cancer Res. 2002 Nov 15; 62:6456–6461. [Accessed 2021 Oct 06]. Available from: https://cancerres.aacrjournals.org/content/62/22/6456
Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004 Jan-Jun;23(1-2):29-39. https://doi.org/10.1023/a:1025806911782
Youssef EM, Chen XQ, Higuchi E, Kondo Y, Garcia-Manero G, Lotan R, et al. Hypermethylation and silencing of the putative tumor suppressor tazaroteneinduced gene 1 in human cancers. Cancer Res. 2004 Apr 1; 64(7):2411-7. https://doi.org/10.1158/0008-5472.can-03-0164
Jones PA. Cancer. Death and methylation. Nature. 2001 Jan 11; 409(6817):141, 143–144. https://doi.org/10.1038/35051677
Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, et al. An Oral Fixed-Dose Combination of Decitabine and Cedazuridine in Myelodysplastic Syndromes: A Multicentre, Open-Label, Dose-Escalation, Phase 1 Study. Lancet Haematol. 2019 Apr; 6(4):e194-e203. https://doi.org/10.1016/s2352-3026(19)30030-4
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al Safety and Preliminary Efficacy of Venetoclax With Decitabine or Azacitidine in Elderly Patients With Previously Untreated Acute Myeloid Leukaemia: A Non-Randomised, Open-Label, Phase 1b Study. Lancet Oncol . 2018 Feb; 19(2):216-228. https://doi.org/10.1016/s1470-2045(18)30010-x
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