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Prediction of anticancer effect of 1-p-D-arabinofuranosylcytostee by sensitive monitoring of its intracellular active metabolite in leukemic cells

通过灵敏监测白血病细胞内的活性代谢物来预测 1-p-D-arabinofuranosylcytostee 的抗癌作用

基本信息

批准号：
10670938
负责人：
UEDA Takanori
金额：
$ 1.02万
依托单位：
Fukui Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

1. Pharmacokinetic study of ara-CTP, an intracellular active metabolite of ara-C.ara-CTP was measured in leukemic cells by the newly established sensitive method in 25 leukemic patients receiving ara-C or log-acting ara-C, BHAC at low or conventional doses. The ara-CTP concentrations differed by the administration methods, doses, and patients, and were not predicted from the plasma ara-C concentrations. As the maintenance of the plasma ara-C was important for the retention of ara-CTP in the cell, continuous infusion of ara-C and BHAC produced ara-CTP efficiently. In BHAC therapy, patients with complete remission achieved greater ara-CTP amounts than those without remission, suggesting that ara-CTP would 6e a crucial parameter for the therapeutic efficacy of BHAC. Myelosuppression was correlated to the plasma ara-C level, suggesting that normal hematopoietic stem cells have similar sensitivity to ara-C among individuals.2. Detection of ara-C incorporated into DNA.The detection method fo … More r ara-C incorporated into DNA was established. DNA was separated from acid insoluble fraction of leukemic cells after treatment with ara-C. The DNA was digested enzymatically to nucleosides that included ara-C. ara-C was isolated by high performance liquid chromatography, followed by liophilization. The recovery of each step was over 90 %. Radioimmunoassay will be applied to the isolated sample using anti-ara-C serum to confirm its ara-C concentration.3. Cytotpxic effects evaluated by a new computer-controlled in vitro pharmacokinetic simulation system.Cytotoxicity was compared between a pharmacokinetically simulated condition and a conventional culture system condition. The survival rates of the cell line K562 incubated with the simulated ara-C infusions for 2, 4, 8, and 16 h demonstrated that the cytotoxicity of ara-C was time-dependent. In contrast, under a conventional culture system, no time-dependent inhibition was observed. Similarly, the simulations of the infusion of daunorubicin for 0.5, 2, 4, and 8 h revealed that the cytotoxic effect of daunorubicin was concentration-dependent Less

1.用新建立的灵敏方法测定了阿糖胞苷的细胞内活性代谢物Ara-CTP在25例白血病患者体内的药代动力学。Ara-CTP浓度因给药方法、剂量和患者的不同而不同，不能根据血浆Ara-C浓度进行预测。由于血浆Ara-C的维持对Ara-CTP在细胞内的保留非常重要，因此持续输注Ara-C和BHAC可有效地产生Ara-CTP。在BHAC治疗中，完全缓解的患者比未缓解的患者获得更多的Ara-CTP，这表明Ara-CTP将是BHAC疗效的关键参数。结论：1.骨髓抑制与血浆Ara-C水平相关，提示正常造血干细胞对Ara-C的敏感性与个体相似。DNA中阿糖胞苷的检测--…的检测方法更多的rAra-C被整合到DNA中。用阿糖胞苷(Ara-C)处理白血病细胞，从酸不溶部分中提取DNA。DNA被酶消化成包括Ara-C在内的核苷。经高效液相色谱分离，再经脂肪干化分离得到阿糖胞苷。各步回收率均在90%以上。用抗Ara-C血清对分离的样品进行放射免疫分析，以确定其Ara-C浓度。用一种新的计算机控制的体外药代动力学模拟系统评价细胞毒性。比较了药物动力学模拟条件和常规培养系统条件下的细胞毒性。模拟阿糖胞苷与K562细胞孵育2、4、8、16h的存活率表明，阿糖胞苷的细胞毒作用具有时间依赖性。相反，在常规培养系统下，没有观察到时间依赖的抑制。类似地，对柔红霉素输注0.5、2、4和8小时的模拟显示，柔红霉素的细胞毒性效应对浓度的依赖性较小