Phase and cell cycle specificity of pyrazofurin action.
Phase and cell cycle specificity of pyrazofurin action.
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发表时间：
1980-08
期刊：
影响因子：
11.2
通讯作者：
E. Oláh;M. Lui;D. Tzeng;G. Weber
中科院分区：
文献类型：
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作者：
E. Oláh;M. Lui;D. Tzeng;G. Weber
摘要 吡唑呋林以 0.4 µm 的 50% 致死剂量杀死组织培养中的肝癌 3924A 细胞，通过与药物孵育 7 天后细胞的集落形成能力来确定。仅在对数生长期，肝癌细胞对吡唑呋林的细胞毒作用敏感，而对平台期细胞没有可检测到的影响。在对数生长期，用吡唑呋林处理培养物 1 或 2 小时，产生双相剂量反应曲线。在同步肿瘤细胞培养中，对吡唑呋林敏感的细胞是处于周期早期G 1 和早S 期的细胞。尿苷和胞苷保护肝癌 3924A 细胞免受吡唑呋林的细胞毒性作用。在 0.5 µm 吡唑呋林存在下 7 天，等摩尔浓度的尿苷导致 70% 的存活率，5 至 10 µm 尿苷提供完全保护。在 1 µm 吡唑呋林存在的情况下，胞苷 (1.0 mm) 提供 80% 的保护，尿苷 (0.1 mm) 导致 90% 的存活率；次黄嘌呤和尿嘧啶无效。在肝癌3924A细胞中，尿苷和胞苷迅速掺入三氯乙酸不溶物中。尿嘧啶的掺入速度较慢。吡唑呋林将尿苷与核酸的掺入增强2倍，将尿嘧啶掺入核酸增强3倍。在对数生长的肝癌细胞中，吡唑呋林 5'-单磷酸的靶标乳清苷 5'-单磷酸脱羧酶 (EC 4.1.1.23) 的活性比平台期肿瘤细胞中观察到的活性增加了 3.3 倍。在吡唑呋林的致死作用中，生长期和乳清苷5′-单磷酸脱羧酶活性的增加起着重要作用。在保护肿瘤细胞免受药物侵害方面，尿苷和胞苷的快速摄取以及尿苷-胞苷激酶对尿苷和胞苷的高活性和强亲和力具有重要意义。尿嘧啶保护失败与该核苷在这些肝癌细胞中的缓慢掺入有关。
Abstract Pyrazofurin killed hepatoma 3924A cells in tissue culture with a 50% lethal dose of 0.4 µm, as determined by the colony-forming ability of the cells after 7-day incubation with the drug. Only in the logarithmic phase of growth were the hepatoma cells sensitive to the cytotoxic action of Pyrazofurin which had no detectable effect on plateau-phase cells. In the logarithmic growth phase, treatment of the culture with Pyrazofurin for 1 or 2 hr resulted in a biphasic dose-response curve. In synchronized tumor cell cultures, it was shown that the cells sensitive to Pyrazofurin were those in early G 1 and early and mid-S phases of the cycle. Uridine and cytidine protected hepatoma 3924A cells from the cytotoxic action of Pyrazofurin. In the presence of 0.5 µm Pyrazofurin for 7 days, an equimolar concentration of uridine resulted in 70% survival, and 5 to 10 µm uridine provided complete protection. In the presence of 1 µm Pyrazofurin, cytidine (1.0 mm) provided 80% protection, and uridine (0.1 mm) resulted in 90% survival; hypoxanthine and uracil were ineffective. In hepatoma 3924A cells, uridine and cytidine were rapidly incorporated into trichloroacetic acid insoluble material. Uracil was incorporated at a slower rate. Pyrazofurin enhanced the incorporation of uridine into nucleic acids 2-fold and that of uracil 3-fold. In the logarithmically growing hepatoma cells, the activity of orotidine 5′-monophosphate decarboxylase (EC 4.1.1.23), the target of Pyrazofurin 5′-monophosphate, was increased 3.3-fold over that observed in the plateau-phase tumor cells. In the lethal effect of Pyrazofurin, the growth phase and the increased activity of orotidine 5′-monophosphate decarboxylase play an important role. In the protection of the tumor cells from the drug, the rapid uptake of uridine and cytidine and the high activity and strong affinity of uridine-cytidine kinase towards uridine and cytidine are significant. In the failure of protection by uracil, the slow incorporation of this nucleoside in these hepatoma cells is relevant.