Establishment of taylor-made therapy of acute leukemia by means of pharmacogenetics

建立药物遗传学治疗急性白血病泰勒制疗法

基本信息

批准号：
15590999
负责人：
UEDA Takanori
金额：
$ 2.24万
依托单位：
University of Fukui (2004-2005)福井医科大学 (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Two strategies for taylor-made therapy with a major antileukemic agent cytarabine (Ara-C) by means of pharmacogenetics were studied.(1) The crucial metabolite for ara-C is the DNA-incorporared ara-C in leukemic cells. Therapeutic drug monitoring at the DNA level in leukemic cells may optimize the chemotherapy for acute leukemia and improve clinical outcome. We presently developed a sensitive new method for monitoring ara-C incorporated into DNA in vivo. Accuracy, precision, and coefficient of variation of the method were excellent. The method was found to determine ara-C incorporation into DNA of ara-C-treated HL60 cells in vitro, the values of which were compatible with those measured by scintillation counting in parallel experiments using tritiated ara-C. Our method could monitor DNA-incorporated ara-C concentrations during intermediate-dose ara-C therapy, together with plasma ara-C and intracellular ara-C triphosphate concentrations. ara-C incorporation into DNA appeared to be assoc … More iated with the intracellular retention of ara-C triphosphate or persistence of the plasma ara-C. Thus, the present method is sensitive, accurate, precise, and may permit therapeutic drug monitoring at the DNA level for better individualization of antileukemic regimens.(2) cDNA microarray was used to examine the comprehensive expression levels of genes in hematologic cell lines in relation to resistance to Ara-C. We isolated five Ara-C resistant cell lines from its parent cell lines (THP-1, K562, HL60, CEM, U937), and conducted molecular cytogenetic analysis of them. Using a quantitative analysis of mRNA expression within these Ara-C reisistant cell lines, we showed no common gene expression to determine resistantce to Ara-C. Each cell lines demonstrated different cross-resistance, despite employment of the common method to induce resistance to Ara-C. These findings suggest the mechanism of resistance of hematological cell lines to Ara-C was varied among each cell lines, which was useful information for the taylor-made therapy with Ara-C. Less

用药物遗传学的泰勒制造的两种抗白血病药物（ARA-C）的策略是在白血病细胞中的DNA CONALATICS。细胞的急性白血病的化学疗法并改善了将ARA-C纳入DNA的新方法。 ARA-C处理的HL60细胞在平行的实验中使用TriTiped Ara-C进行了闪烁，我们的方法是coud监测器中的ARA-C浓度。相关……与ara-c三磷酸盐或血浆ara-c的内在缩放相关。与ARA-C相关的血液细胞系。 ANTCE对ARA-C。尽管使用了对Ara-C的抗性，但使用了对Ara-C的耐药性，但在每个细胞lins中都有不同的抗性。用于泰勒制造的Ara-C治疗