【摘 要】
：
Myelodysplastic syndromes (MDS) are characterized by pancytopenias and immature production of red blood cells by the bone marrow.Decitabine (DAC) is approved by FDA for the treatment of this disease,b
【机 构】
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Department of Leukemia The University of Texas M.D.Anderson Cancer Center USA
【出 处】
：
中国上海第七届国际新药发明科技年会
论文部分内容阅读
Myelodysplastic syndromes (MDS) are characterized by pancytopenias and immature production of red blood cells by the bone marrow.Decitabine (DAC) is approved by FDA for the treatment of this disease,but resistance to DAC develops during treatment and mechanisms of resistance remain unknown.Therefore,we investigated mechanisms of the primary and secondary resistance to DAC in MDS patients.We initially did Quantitative Real-Time PCR of a group of genes that were related to DAC metabolism.There were no significant changes of these gene expression in patients at diagnosis and after relapse (P>0.05) and deoxycytidine kinase gene (DCK) mutations were not detected in all the patients after relapse,whereas there was 3.2 fold higher CDA/DCK in non-responders than responders in patients with the primary resistance (P=0.027).Furthermore,we found that CDA/DCK was inversely correlated with DAC hypomethylation induction of long interspersed nuclear elements (LINE) on day 5 (P=0.04),suggesting that non responders actually were withstanding more hypomethylation than responders.In search for mechanisms of the secondary resistance to DAC,we next performed Methylation Microarray Analysis of 9008 autosomal genes in 4 patients,which showed no significant difference of global gene methylation between diagnosis and after relapse (P>0.05).Methylation of P15,Olig2,PGRA,PGRB,Cadherin 13,miR-124aland LINE were validated by pyrosequencing analysis in 20 patients.Consistently,DNA methytransferase expression (DNMT1,3a and 3b) were not significantly changed between diagnosis and after relapse (P>0.05).Finally,cytogenetics showed that 18% of patients developed aberrant progression including +8,del 16q,and-7 after relapse.These results show that the primary resistance to DAC in MDS might be due to pharmacological mechanisms related to aberrant DAC metabolism,whereas the secondary resistance to DAC might be due to downstream pathways such as chromosome changes in a subset of MDS patients..
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