去甲基化药物在骨髓增生异常综合征治疗中的进展
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摘要
骨髓增生异常综合征(myelodysplastic syndrome,MDS)是起源于造血干细胞的一组异质性髓系克隆性疾病,具有较高的急性髓系白血病转化风险。MDS患者自然病程及预后的异质性很大,必须根据患者的预后分层制定个体化治疗方案。目前去甲基化药物是高危MDS患者治疗的主要手段之一。本文总结归纳了目前具有代表性的去甲基化药物的研究进展,期望对该类药物的临床应用和研究提供参考信息。
Myelodysplastic syndrome(MDS) is a group of heterogeneous myeloid clonal diseases originated from hematopoietic stem cells and has a high risk to transform into acute myeloid leukemia. The natural course and prognosis of MDS patients are highly heterogeneous, and individualized treatment plans must be developed according to the stratification of patients' prognosis. Currently, hypomethylating agents are one of the main treatments for high-risk MDS patients. This paper summarizes the research progress of representative hypomethylating agents in recent years,and hopes to provide references for the clinical application and research of these drugs.
Myelodysplastic syndrome(MDS) is a group of heterogeneous myeloid clonal diseases originated from hematopoietic stem cells and has a high risk to transform into acute myeloid leukemia. The natural course and prognosis of MDS patients are highly heterogeneous, and individualized treatment plans must be developed according to the stratification of patients' prognosis. Currently, hypomethylating agents are one of the main treatments for high-risk MDS patients. This paper summarizes the research progress of representative hypomethylating agents in recent years,and hopes to provide references for the clinical application and research of these drugs.
引文
[1]中华医学会血液学分会.骨髓增生异常综合征诊断与治疗中国专家共识[J].中华血液学杂志,2014,11(35):1024-1048.
[2]Canaani J,Nagler A.Established and emerging targeted therapies in the myelodysplastic syndromes[J].Expert Rev Hematol,2016,9(10):997-1005.
[3]Ades L,Itzykson R,Fenaux P.Myelodysplastic syndromes[J].Lancet,2014,383(9936):2239-2252.
[4]Itzykson R,Fenaux P.Epigenetics of myelodysplastic syndromes[J].Leukemia,2014,28(3):497-506.
[5]Qin Y Z,Zhang Y H,Qin X Y,et al.Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes[J].Oncol Lett,2017,13(4):2823-2830.
[6]Zhang Q,Lin Z,Yin X,et al.In vitro and in vivo study of hydralazine,a potential anti-angiogenic agent[J].Eur J Pharmacol,2016,779:138-146.
[7]Halby L,Champion C,Senamaud-Beaufort C,et al.Rapid synthesis of new DNMT inhibitors derivatives of procainamide[J].Chembiochem,2012,13(1):157-165.
[8]Wang Y,Li Y,Liu X,et al.Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents[J].Curr Cancer Drug Targets,2013,13(5):506-518.
[9]Zwergel C,Valente S,Mai A.DNA Methyltransferases Inhibitors from Natural Sources[J].Curr Top Med Chem,2016,16(7):680-696.
[10]Fulkerson C M,Dhawan D,Jones D R,et al.Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs[J].Vet Comp Oncol,2017,15(1):226-236.
[11]Yun S,Vincelette N D,Abraham I,et al.Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome:a systematic review of hypomethylating agents trials[J].Clinical7Epigenetics,2016,8(1):1-9.
[12]Nakamura K,Nakabayashi K,Htet Aung K,et al.DNA Methyltransferase Inhibitor Zebularine Induces Human Cholangiocarcinoma Cell Death through Alteration of DNA Methylation Status[J].PLOS ONE,2015,10(3):e120545.
[13]Lee J,Kim Y,Sohn S K,et al.Benefits of hypomethylating therapy in IPSS lower-risk myelodysplastic syndrome patients:A retrospective multicenter case series study[J].Leukemia Research,2017,60(60):135-144.
[14]Gore S D,Fenaux P,Santini V,et al.A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001trial[J].Haematologica,2013,98(7):1067-1072.
[15]Garcia-Manero G.Myelodysplastic syndromes:2015 Update on diagnosis,risk-stratification and management[J].Am J Hematol,2015,90(9):831-841.
[16]Mahfouz R Z,Jankowska A,Ebrahem Q,et al.Increased CDAexpression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy[J].Clin Cancer Res,2013,19(4):938-948.
[17]Chang C,Zhao Y,Xu F,et al.TP53 mutations predict decitabineinduced complete responses[J].British Journal of Haematology,2017,176(4):600-608.
[18]Momparler R L.Pharmacology of 5-Aza-2'-deoxycytidine(decitabine)[J].Seminars in Hematology,2005,42(3 suppl 2):9-16.
[19]Li X,Song Q,Chen Y,et al.Decitabine of reduced dosage in Chinese patients with myelodysplastic syndrome:a retrospective analysis[J].PLo S One,2014,9(4):e95473.
[20]Li H,Wang L,Wu Y,et al.Very-Low-Dose Decitabine Is Effective in Treating Intermediate-or High-Risk Myelodysplastic Syndrome[J].Acta Haematologica,2017,138(3):168-174.
[21]Ye L,Ren Y,Zhou X,et al.Decitabine priming prior to low-dose chemotherapy improves patient outcomes in myelodysplastic syndromes-RAEB:a retrospective analysis vs.chemotherapy alone[J].Journal of Cancer Research and Clinical Oncology,2017,143(5):873-882.
[22]rskov A D,Treppendahl M B,Skovbo A,et al.Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AMLpatients:A rationale for combined targeting of PD-1 and DNAmethylation[J].Oncotarget,2015,6(11):9612-9626.
[23]Prébet T,Gore S D,Esterni B,et al.Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure[J].Journal of Clinical Oncology,2011,29(24):3322-3327.
[24]Sekeres M A.Managing patients with higher-risk myelodysplastic syndrome with stable disease on hypomethylating agents[J].Leuk Lymphoma,2015,56(12):3267-3269.o
[25]Komrokji R S.Treatment of Higher-Risk Myelodysplastic Syndromes After Failure of Hypomethylating Agents[J].Clinical Lymphoma Myeloma and Leukemia,2015,15:S56-S59.
[26]Loiseau C,Ali A,Itzykson R.New therapeutic approaches in myelodysplastic syndromes:Hypomethylating agents and lenalidomide[J].Exp Hematol,2015,43(8):661-672.
[27]Garcia-Manero G,Gore S,Kambhampati S.Efficacy and safety of extended dosing schedules of CC-486[J].Leukemia,2016(30):889-896.
[28]Issa J J,Roboz G,Rizzieri D,et al.Safety and tolerability of guadecitabine(SGI-110)in patients with myelodysplastic syndrome and acute myeloid leukaemia:a multicentre,randomised,doseescalation phase 1 study[J].oncology,2015,16(9):1099-1110.
[29]Kantarjian H M,Roboz G J,Kropf P L,et al.Guadecitabine(SGI-110)in treatment-naive patients with acute myeloid leukaemia:phase 2 results from a multicentre,randomised,phase 1/2 trial[J].Lancet Oncol,2017,18(10):1317-1326.
[30]Shahrabi S,Khosravi A,Shahjahani M,et al.Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy:new insights[J].Oncology Reviews,2016,10(2):311.
[31]Kuendgen A,Bug G,Ottmann O G,et al.Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid[J].Clinical Epigenetics,2011,2(2):389-399.
[32]Issa J,Garcia-Manero G,Huang X,et al.Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia[J].Cancer,2015,121(4):556-561.
[33]Candelaria M,Burgos S,Ponce M,et al.Encouraging results with the compassionate use of hydralazine/valproate(TRANSKRIP)as epigenetic treatment for myelodysplastic syndrome(MDS)[J].Ann Hematol,2017,96(11):1825-1832.
[2]Canaani J,Nagler A.Established and emerging targeted therapies in the myelodysplastic syndromes[J].Expert Rev Hematol,2016,9(10):997-1005.
[3]Ades L,Itzykson R,Fenaux P.Myelodysplastic syndromes[J].Lancet,2014,383(9936):2239-2252.
[4]Itzykson R,Fenaux P.Epigenetics of myelodysplastic syndromes[J].Leukemia,2014,28(3):497-506.
[5]Qin Y Z,Zhang Y H,Qin X Y,et al.Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes[J].Oncol Lett,2017,13(4):2823-2830.
[6]Zhang Q,Lin Z,Yin X,et al.In vitro and in vivo study of hydralazine,a potential anti-angiogenic agent[J].Eur J Pharmacol,2016,779:138-146.
[7]Halby L,Champion C,Senamaud-Beaufort C,et al.Rapid synthesis of new DNMT inhibitors derivatives of procainamide[J].Chembiochem,2012,13(1):157-165.
[8]Wang Y,Li Y,Liu X,et al.Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents[J].Curr Cancer Drug Targets,2013,13(5):506-518.
[9]Zwergel C,Valente S,Mai A.DNA Methyltransferases Inhibitors from Natural Sources[J].Curr Top Med Chem,2016,16(7):680-696.
[10]Fulkerson C M,Dhawan D,Jones D R,et al.Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs[J].Vet Comp Oncol,2017,15(1):226-236.
[11]Yun S,Vincelette N D,Abraham I,et al.Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome:a systematic review of hypomethylating agents trials[J].Clinical7Epigenetics,2016,8(1):1-9.
[12]Nakamura K,Nakabayashi K,Htet Aung K,et al.DNA Methyltransferase Inhibitor Zebularine Induces Human Cholangiocarcinoma Cell Death through Alteration of DNA Methylation Status[J].PLOS ONE,2015,10(3):e120545.
[13]Lee J,Kim Y,Sohn S K,et al.Benefits of hypomethylating therapy in IPSS lower-risk myelodysplastic syndrome patients:A retrospective multicenter case series study[J].Leukemia Research,2017,60(60):135-144.
[14]Gore S D,Fenaux P,Santini V,et al.A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001trial[J].Haematologica,2013,98(7):1067-1072.
[15]Garcia-Manero G.Myelodysplastic syndromes:2015 Update on diagnosis,risk-stratification and management[J].Am J Hematol,2015,90(9):831-841.
[16]Mahfouz R Z,Jankowska A,Ebrahem Q,et al.Increased CDAexpression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy[J].Clin Cancer Res,2013,19(4):938-948.
[17]Chang C,Zhao Y,Xu F,et al.TP53 mutations predict decitabineinduced complete responses[J].British Journal of Haematology,2017,176(4):600-608.
[18]Momparler R L.Pharmacology of 5-Aza-2'-deoxycytidine(decitabine)[J].Seminars in Hematology,2005,42(3 suppl 2):9-16.
[19]Li X,Song Q,Chen Y,et al.Decitabine of reduced dosage in Chinese patients with myelodysplastic syndrome:a retrospective analysis[J].PLo S One,2014,9(4):e95473.
[20]Li H,Wang L,Wu Y,et al.Very-Low-Dose Decitabine Is Effective in Treating Intermediate-or High-Risk Myelodysplastic Syndrome[J].Acta Haematologica,2017,138(3):168-174.
[21]Ye L,Ren Y,Zhou X,et al.Decitabine priming prior to low-dose chemotherapy improves patient outcomes in myelodysplastic syndromes-RAEB:a retrospective analysis vs.chemotherapy alone[J].Journal of Cancer Research and Clinical Oncology,2017,143(5):873-882.
[22]rskov A D,Treppendahl M B,Skovbo A,et al.Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AMLpatients:A rationale for combined targeting of PD-1 and DNAmethylation[J].Oncotarget,2015,6(11):9612-9626.
[23]Prébet T,Gore S D,Esterni B,et al.Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure[J].Journal of Clinical Oncology,2011,29(24):3322-3327.
[24]Sekeres M A.Managing patients with higher-risk myelodysplastic syndrome with stable disease on hypomethylating agents[J].Leuk Lymphoma,2015,56(12):3267-3269.o
[25]Komrokji R S.Treatment of Higher-Risk Myelodysplastic Syndromes After Failure of Hypomethylating Agents[J].Clinical Lymphoma Myeloma and Leukemia,2015,15:S56-S59.
[26]Loiseau C,Ali A,Itzykson R.New therapeutic approaches in myelodysplastic syndromes:Hypomethylating agents and lenalidomide[J].Exp Hematol,2015,43(8):661-672.
[27]Garcia-Manero G,Gore S,Kambhampati S.Efficacy and safety of extended dosing schedules of CC-486[J].Leukemia,2016(30):889-896.
[28]Issa J J,Roboz G,Rizzieri D,et al.Safety and tolerability of guadecitabine(SGI-110)in patients with myelodysplastic syndrome and acute myeloid leukaemia:a multicentre,randomised,doseescalation phase 1 study[J].oncology,2015,16(9):1099-1110.
[29]Kantarjian H M,Roboz G J,Kropf P L,et al.Guadecitabine(SGI-110)in treatment-naive patients with acute myeloid leukaemia:phase 2 results from a multicentre,randomised,phase 1/2 trial[J].Lancet Oncol,2017,18(10):1317-1326.
[30]Shahrabi S,Khosravi A,Shahjahani M,et al.Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy:new insights[J].Oncology Reviews,2016,10(2):311.
[31]Kuendgen A,Bug G,Ottmann O G,et al.Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid[J].Clinical Epigenetics,2011,2(2):389-399.
[32]Issa J,Garcia-Manero G,Huang X,et al.Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia[J].Cancer,2015,121(4):556-561.
[33]Candelaria M,Burgos S,Ponce M,et al.Encouraging results with the compassionate use of hydralazine/valproate(TRANSKRIP)as epigenetic treatment for myelodysplastic syndrome(MDS)[J].Ann Hematol,2017,96(11):1825-1832.