Raj K, John A, Ho A, Chronis C, Khan S, Samuel J, Pomplun S, Thomas N S B, Mufti G J
King's College London, Department of Haematological Medicine, Denmark Hill Campus, London, UK.
Leukemia. 2007 Sep;21(9):1937-44. doi: 10.1038/sj.leu.2404796. Epub 2007 Jul 5.
5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.
5-氮杂胞苷是一种DNA甲基转移酶抑制剂，对骨髓增生异常综合征（MDS）患者有效。5-氮杂胞苷的疗效是通过关键基因的去甲基化还是细胞毒性实现尚不清楚。在34例接受5-氮杂胞苷治疗的MDS或急性髓系白血病（AML）患者中，7例实现完全缓解（CR）（21%），6例血液学改善。血液学改善（HI）时，所有6例患者骨髓（BM）原始细胞均少于5%（2例原有难治性贫血（RA），4例伴有过多原始细胞的难治性贫血（RAEB））。另1例RAEB患者原始细胞减少至5%以下但无血液学改善。7例完全缓解者中有5例（71%）存在7号染色体异常。BM CR预示总生存期（OS）更长（中位生存期23个月对9个月，P=0.015）。对CDKN2B（p15(INK4b)）启动子进行亚硫酸氢盐基因组测序（BGS）显示，在14/17例（82%）分析的患者中，预处理甲基化水平低且不均一（平均12.2%）。缓解者基线甲基化水平较低（9.8%对未缓解者的16.2%，P=0.07）。甲基化>24%的患者无反应，这些患者中p15(INK4b) mRNA未表达。5-氮杂胞苷使8/17例（47%）患者的CDKN2B甲基化平均降低6.8%，但这与反应无关。在75 mg/m²剂量下，细胞死亡（BM细胞减少（P=0.001）和凋亡增加（P=0.02））而非CDKN2B去甲基化与反应相关。甲基化>24%的患者可能从替代给药或联合策略中获益。
