细胞周期蛋白E-cdk2激活与细胞周期阻滞和抑制DNA复制thymidylate合成酶抑制剂Tomudex诱导。

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阴MB,郭B, Panadero, Frank C Wrzosek C,斯洛克姆港元,Rustum

细胞周期蛋白E-cdk2激活与细胞周期阻滞和抑制DNA复制thymidylate合成酶抑制剂Tomudex诱导。

细胞实验研究》1999年2月25日,247 (1):189 - 99。

PubMed ID

10047461 (在PubMed

]

文摘

Tomudex (ZD1694)是一种特定antifolate-based thymidylate合成酶抑制剂活跃在各种实体瘤的恶性肿瘤。研究进行了体外评价下游分子改变诱导结果强有力的和持续的抑制thymidylate Tomudex合成酶。在最初2 h Tomudex治疗后24小时,人类A253头颈部鳞状细胞癌的细胞,不是p53、p21表达(WAF1)与DNA含量积累的年代早期阶段的特征与相应细胞的细胞周期G1和G2 / M期。细胞周期蛋白和cdk蛋白质表达的变化及其激酶活动进行控制和药物治疗A253细胞。Tomudex治疗导致的减少p27 (kip1)表达与细胞周期素E和cdk2蛋白表达和激酶活动后24 h 2 h曝光。尽管细胞周期素蛋白表达明显增加,细胞周期蛋白激酶活性只是略有增加。细胞周期蛋白D1,细胞周期蛋白B,到,cdc2蛋白表达和激酶活动保持不变。缺乏激活细胞周期蛋白和B-cdc2与G2 / M期细胞比例降低。增加细胞周期蛋白E-cdk2蛋白表达伴随着DNA合成的抑制作用,与减少E2F-1表达式。这些结果提出,细胞周期蛋白E-cdk2激酶可以负调节DNA复制。 The studies with dThyd rescue from cyclin E-cdk2 protein overexpression and growth inhibition by Tomudex indicate that increased cyclin E-cdk2 protein expression is associated with effective inhibition of thymidylate synthase and resultant dNTP pool imbalance. Provision of dThyd more than 24 h after exposure to Tomudex allowed cells to replicate DNA for a single cycle back to G1, but did not prevent the profound growth-inhibitory effect manifested in the following 5 days. Tomudex treatment resulted in a time-dependent induction of the megabase DNA fragments, followed by secondary 50- to 300-kb DNA fragmentation. The 50- to 300-kb DNA fragmentation may be derived from the inhibition of DNA synthesis associated with cyclin E-cdk2 activation. These results suggest that the megabase DNA fragmentation is induced as a consequence of inhibition of thymidylate synthase by Tomudex and kilobase DNA fragmentation may correlate with the reduction of p27(kip1) expression and the increase in cyclin E and cdk2 kinase activities. Activation of cyclin E and cdk2 kinases allows cells to transit from G1 to S phase accompanied by the inhibition of DNA synthesis. The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent.

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药物靶点

药物	目标	类	生物	药理作用	行动
Raltitrexed	Thymidylate合酶	蛋白质	人类	是的	抑制剂	细节