Prediction of anticancer effect of 1-p-D-arabinofuranosylcytostee by sensitive monitoring of its intracellular active metabolite in leukemic cells
Prediction of anticancer effect of 1-p-D-arabinofuranosylcytostee by sensitive monitoring of its intracellular active metabolite in leukemic cells
批准号:
10670938
负责人:
UEDA Takanori
金额:
$1.02万
依托单位:
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
项目状态:
已结题
起止时间:
1998 至 2001
中文摘要
1. ara-C胞内活性代谢物ara-CTP的药代动力学研究。在25例接受低剂量或常规剂量ara-C或对数作用ara-C、BHAC治疗的白血病患者中,采用新建立的敏感方法测定白血病细胞中的ara-CTP。ara-CTP浓度因给药方法、剂量和患者而异,并且不能从血浆ara-C浓度预测。由于血浆中ara-C的维持对细胞中ara-CTP的保留至关重要,因此连续输注ara-C和BHAC可以有效地产生ara-CTP。在BHAC治疗中,完全缓解的患者获得的ara-CTP量高于未缓解的患者,这表明ara-CTP将是BHAC治疗效果的关键参数。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具有相似的个体敏感性。DNA中ara-C的检测。建立了DNA中更多r - ara-C的检测方法。经ara-C处理后,从白血病细胞的酸不溶性部分中分离出DNA。DNA被酶消化成核苷,其中包括ara-C。采用高效液相色谱法分离ara-C,并进行油干分离。各步骤回收率均在90%以上。用抗ara-C血清对分离样品进行放射免疫测定,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作用。比较了药代动力学模拟条件和常规培养系统条件下的细胞毒性。模拟ara-C输注2、4、8和16 h后K562细胞株的存活率表明ara-C的细胞毒性具有时间依赖性。相比之下,在常规培养系统中,没有观察到时间依赖性抑制。同样,模拟输注柔红霉素0.5、2、4和8 h的细胞毒作用显示柔红霉素的浓度依赖性较弱
英文摘要
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
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Haruyuki Takemura: "Cross-resistance to ara-C and daunorubicin Induced by slimultaneous treatment with both drugs showed a combination-spesific mechanism in HL60/AD Ccells."AACR 91st Annual Meeting Proceedings.. 762-762 (2000)
Haruyuki Takemura:“两种药物同时治疗引起的对 ara-C 和柔红霉素的交叉耐药性在 HL60/AD C 细胞中显示出组合特异性机制。”AACR 第 91 届年会论文集.. 762-762 (2000)
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Haruyuki Takemura: "Simultaneous treatment with 1-β-D-arabinofuranosylcytosine and daunorubicin induces cross-resistance to both drugs due to a combination-specific mechanism in HL60 cells"Cancer Res.. 61. 172-177 (2001)
Haruyuki Takemura:“由于 HL60 细胞中的组合特异性机制,同时使用 1-β-D-阿拉伯呋喃糖基胞嘧啶和柔红霉素治疗会诱导对两种药物的交叉耐药性”Cancer Res.. 61. 172-177 (2001)
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Takahiro Yamauchi: "Monitoring of intracellular 1-β-D-arabinofuranosyloytosine 5'-triphosphate in 1-β-D-arabinofuranosylcytosine therapy at low-and conventional-doses"Jpn. J. Cancer Res.. 92. 546-553 (2001)
Takahiro Yamauchi:“低剂量和常规剂量的 1-β-D-阿拉伯呋喃糖基胞嘧啶治疗中细胞内 1-β-D-阿拉伯呋喃糖基胞嘧啶 5-三磷酸的监测”Jpn. Cancer Res. 92. 546-553 (2001) )
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Toshihiro Fukushima: "A pharmacokinetic study of idarubicin in Japanese patients with malignant lymphoma : relationship with leukocytopenia and neutropenia"Int. J. Hematol.. 74. 297-302 (2001)
Toshihiro Fukushima:“日本恶性淋巴瘤患者中伊达比星的药代动力学研究:与白细胞减少症和中性粒细胞减少症的关系”Int。
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Takanori Ueda: "Purine and Pyrimidine Metabolism in Man IX" Plenum Publishing Corporation, 866 (1998)
Takanori Ueda:“人类 IX 中的嘌呤和嘧啶代谢” Plenum Publishing Corporation,866(1998)
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