生物信息学方法优化依硫磷酸联合方案治疗骨髓增生异常综合征的应用研究

目的 采用生物信息学方法分析依硫磷酸治疗骨髓增生异常综合征(MDS)的机制,据此优化依硫磷酸联合方案治疗MDS.方法 (1)生物信息学方法:利用开放性的人类基因组表达数据库和互联网平台.①分析依硫磷酸调控人类基因组表达谱的变化和MDS人类基因组表达谱的特点;②筛选依硫磷酸可能作用的靶基因,据此预测联合用药的可行性;③采用人类基因组表达谱相似性分析的方法,预测可能具有治疗MDS作用的药物.(2)临床研究:以传统方法治疗无效的MDS患者(WHO分型)为对象,共18例患者(男17例,女1例),其中难治性贫血(RA)7例,难治性贫血伴环型铁粒幼细胞增多(RARS)2例,难治性血细胞减少症伴有多系发育异常(RCMD)9例,中位年龄79岁.采用依硫磷酸联合重组人红细胞生成素(rhEPO)方案治疗,具体用药为:依硫磷酸静滴0.4 g/d,每周5 d,连续4周,rhEPO皮下注射6000IU,每周3次.停药2周后评估疗效.结果 依硫磷酸对人类基因组2.6%的基因具有调控作用,其中主要是凋亡、细胞周期和分化有关的基因,包括促进EPO通路下游功能基因ELKI表达和抑制细胞周期D1表达的作用.依硫磷酸联合EPO方案治疗MDS,红系、粒系和血小板反应率分别为83.3%、66.7%和55.6%.结论 在筛选依硫磷酸调控的靶基因和优化骨髓增生异常综合征治疗方案方面,生物信息学方法具有方便、快捷、经济和有效的优点,可作为一种补充手段用于MDS发病机制和临床治疗的研究.

Application of bioinformatics analysis to optimize amifostine combination therapeutic regimen of myelodysplastic syndrome

Objective To apply bioinformatics analysis to study the potential mechanism of amifostine for the treatment of myelodysplastie syndrome (MDS) and optimize amifostine combination regimen to further improve the efficacy and prognosis of MDS. Methods Bioinformatics analysis: internetbased human gene expression open database was used to predict the genomic profiling by regulation of amifostine and gene expression of MDS. And then possible target genes of amifostine were screened to predict the feasibility of amifostine combination regimen. Finally, similar analysis of gene expression profiling was conducted to forecast the potential therapeutic drugs for MDS. Clinical investigation: eighteen patients with MDS, non-responding to traditional drugs, were enrolled. According to the latest WHO classification, the patients were divided into 7 patients of refractory anemia (RA), 2 patients of refractory anemia with ring siderublust (RAILS) and 9 patients of refractory cytopenia with multilineage dysplasia (RCMD).Distributions of age was 19-91 years old (mean: 79). There were 17 males and 1 female. The regimen of amifostine plus recombinant human erythropoietin (rhEPO) was used to treat the MDS patients.Administration formula was as follows : the intravenous drip of amifostine at a dosage of 0.4 gram per day was given 5 days weekly for 4 consecutive weeks ; the subcutaneous injection of rhEPO at a dosage of 6 000 IU was given 3 times weekly. Therapeutic effect was evaluated 2 weeks post-therapy. Results Approximately 2.6 percent of human gene involved in apoptosis, cell cycle and differentiation was regulated by amifostine.Especially, upregnlation of ELK1 expression, which belongs to downstream functional gene of EPO pathway,and downregulation of Cyclin D1 expression were successfully predicted. Based on the potential therapeutic mechanism amifostine for MDS, amifostine plus EPO had dual effects on MDS, i. e. promotion of hematopoiesis and inhibition of tumor cell proliferation. Clinical investigation showed that the response rates of hemoglobin, neutrophil and platelet were 83.3% , 66.7% and 55.6% respectively. The results suggested that the regimen of amifostine plus EPO had better therapeutic effects than a single agent. Conclusions The study successfully used bioinformaties analysis to screen target genes regulated by amifostine and optimize amifostine combination therapeutie regimen for MDS. Bioinformatics method is a convenient,economical and effective supplementary approach for studying the pathogenesis and therapeutics of MDS.