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Intracellular metabolism and mechanism of action of antileukemic agents studied by means of automatic simulation system of drug concentration.

利用药物浓度自动模拟系统研究抗白血病药物的细胞内代谢及作用机制。

基本信息

批准号：
06671083
负责人：
UEDA Takanori
金额：
$ 1.34万
依托单位：
Fukui Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

It is very important to study the metabolism and action of antileukemic agents under the condition which precisely reflect the clinical pharmacokinetics. In this year, we studied cell growth inhibition of leukemic cell line (K562) by cytosine arabinoside (ara-C), using method of trypan blue dye exclusion assay (TB) and clonogenic assay (CA) under the drug concentration regulated by automatic simulation system which was established last year. Under the condition of clinically regular dose ara-C (100mg/m_2) and equal area under the curve (AUC) each other, the cell growth by 2,4,8,16 hour infusion was 73%, 53%, 39%, 45% using TB,and 76%, 72%, 34%, 15% using CA respectively, compared with control. More obvious time dependent inhibition by ara-C was observed using CA.We also compared the effect of daunorubicin (DNR) by simulation method with the data by conventional culture system. The cell growth was 82% of the control using CA under simulated condition with DNR 40mg/m_2 30min.infusion (Cmax ; 0.20 muM,t1/2beta ; 4.35 hr). On the other side, 0.022 muM was required to get the same growth inhibition effect by 24 hours incubation under condition of conventional culture system. About 9 times higher concentration was required in automatic simulation system compared with conventional culture system. This result was different from the the case with the ara-C in last year where the difference was about 80 times, suggesting the difference might depend on the action and metabolism of each drug. In addition, it was suggested that to estimate the anti-tumor effect of drug, automatic simulation system is superior than conventional culture system. And it was also suggested that CA was better method than TB to judge the cell growth inhibition effect. Now we are studying cell growth inhibition under condition to simulate ara-C and DNR simultaneously using automatic simulation system.

在准确反映临床药代动力学的条件下，研究抗白血病药物的代谢和作用具有重要意义。本研究采用台盼蓝拒染法(TB法)和克隆形成法(CA法)研究了阿糖胞苷(Ara-C)对白血病细胞株K562细胞生长的抑制作用。在临床常规剂量Ara-C(100 mg/m_2)和等曲线下面积(AUC)条件下，TB输注2、4、8、16h的细胞生长分别为对照组的73%、53%、39%、45%，CA分别为76%、72%、34%、15%。用CA法观察到Ara-C的时间依赖性抑制作用更明显，并将柔红霉素(DNR)的作用效果与常规培养系统的数据进行了比较。在模拟条件下，加入柔红霉素40 mg/m_2，30min(Cmax：0.20um，t1/2beta；4.35hr)，细胞生长率为对照组的82%。而在常规培养条件下，需要0.022微米培养24小时才能达到同样的生长抑制效果。与常规培养系统相比，自动模拟系统所需的浓度约高9倍。这一结果与去年Ara-C的情况不同，后者的差异约为80倍，这表明差异可能取决于每种药物的作用和代谢。此外，在评价药物的抗肿瘤效果时，自动模拟系统优于常规培养系统。提示CA法比TB法更好地判断细胞生长抑制效果。目前，我们正在利用自动模拟系统同时模拟Ara-C和DNR的条件下进行细胞生长抑制研究。