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首页> 外文期刊>Archives of Toxicology >Cytotoxicity of cyclophosphamide, paclitaxel, and docetaxel for tumor cell lines in vitro: effects of concentration, time and cytochrome P450-catalyzed metabolism.
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Cytotoxicity of cyclophosphamide, paclitaxel, and docetaxel for tumor cell lines in vitro: effects of concentration, time and cytochrome P450-catalyzed metabolism.

机译：环磷酰胺，紫杉醇和多西紫杉醇对肿瘤细胞的体外细胞毒性：浓度，时间和细胞色素P450催化代谢的影响。

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Cytotoxic effects of cyclophosphamide (CPA), paclitaxel (PCT), and docetaxel (DTX) and their modulation by cytochrome P450 (CYP) metabolism were studied by incubating cell lines L929 and P388D1 with or without rat liver microsomes. The microsomes themselves were not cytotoxic. P388D1 cells were more sensitive to CPA, PCT, and DTX than L929 cells. CYP2B1-, CYP3A-, and CYP2E1-induced microsomes effectively oxidized the prodrug CPA to cytotoxic products in 2-h incubation periods. Cytotoxicity of DTX and PCT for P388D1 cells became apparent 24 h after a 2-h incubation period with the drugs, and their effects were enhanced by CYP2E1 microsomes, but markedly decreased by CYP3A-induced microsomes. DTX and PCT without microsomes caused a dose-related cytotoxicity in P388D1 and HeLa cells. P388D1 and HeLa cells did not grow after a 24-h exposure to 1-10 microM DTX, but about 0.1% of cells survived exposure to 1-10 microM PCT. After 4 weeks of multiplication, the surviving P388D1 cells displayed lower sensitivity to DTX and PCT, but cytotoxicity in HeLa cells was unchanged and their growth ability decreased. In P388D1 cells, PCT with DTX (0.1, 0.5. 1, 2.5, or 5 microM) showed only additive cytotoxicity, although they reportedly act in different phases of the cell cycle. In P388D1 cells treated with DTX or PCT, normal mononuclear cells disappeared and the cell diameter increased up to threefold. Mulberry-like nuclei developed, giving rise to multiple nuclei, which were hyper- or hypochromatic. Chromatin condensation in some multiple nuclei and cell shrinkage of some cells fit the definition of apoptosis, but enlargement of the surviving cells and numerous hypochromatic nuclei do not. In conclusion, L929 and P388D1 cells incubated with microsomes enabled the role of various CYP enzymes in the effect of anticancer drugs to be assessed. The delayed cytotoxicity of DTX and PCT compared to that of CPA was related to their different mode of action. Fluorescent microscopy revealed quantitatively different effects of PCT and DTX on the nuclei, indicating that their mode of action may not be completely identical.
机译：通过在有或没有大鼠肝微粒体的情况下孵育L929和P388D1细胞系，研究了环磷酰胺（CPA），紫杉醇（PCT）和多西紫杉醇（DTX）的细胞毒作用及其通过细胞色素P450（CYP）代谢的调节。微粒体本身没有细胞毒性。与L929细胞相比，P388D1细胞对CPA，PCT和DTX更为敏感。 CYP2B1，CYP3A-和CYP2E1诱导的微粒体在2小时的潜伏期中将前药CPA有效氧化为细胞毒性产物。与药物孵育2小时后24小时，DTX和PCT对P388D1细胞的细胞毒性变得明显，并且其作用被CYP2E1微粒体增强，但被CYP3A诱导的微粒体显着降低。没有微粒体的DTX和PCT在P388D1和HeLa细胞中引起剂量相关的细胞毒性。暴露于1-10 microM的DTX 24小时后，P388D1和HeLa细胞未生长，但暴露于1-10 microM的PCT中存活了约0.1％的细胞。繁殖4周后，存活的P388D1细胞对DTX和PCT的敏感性降低，但HeLa细胞的细胞毒性未变，其生长能力下降。在P388D1细胞中，具有DTX（0.1、0.5、1、2.5或5 microM）的PCT仅显示出附加的细胞毒性，尽管据报道它们在细胞周期的不同阶段起作用。在用DTX或PCT处理的P388D1细胞中，正常的单核细胞消失了，细胞直径增加了三倍。形成了桑树状的核，产生了多核或低色的多个核。染色质在某些多核中的凝缩和某些细胞的细胞缩小符合凋亡的定义，但存活细胞的扩大和许多色素减退的核不适合。总之，与微粒体一起孵育的L929和P388D1细胞能够评估各种CYP酶在抗癌药物作用中的作用。与CPA相比，DTX和PCT的延迟细胞毒性与它们的不同作用方式有关。荧光显微镜揭示了PCT和DTX对细胞核的定量影响，表明它们的作用方式可能不完全相同。

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