Helmholtz Center Munich, German Research Center for Environmental Health, Marchioninistrasse 25, D-81377 München, Germany.
Anticancer Res. 2013 Dec;33(12):5273-87.
BACKGROUND/AIM: Anthracyclines have been proven able to reduce the activity of vinca alkaloids by induction of cell-cycle arrest. The present study aims at identifying the critical initiation steps of signal transduction which transduce the inhibitory effects on the cytotoxicity of vinca alkaloids.
Several new cytostatic drug classes were evaluated together with vincristine in tumor cell lines and patients' tumor cells. RNA interference was used for molecular analyses.
Inhibition of vincristine was observed by all cytostatic drugs, which induced cell-cycle arrest. Knockdown of proteins of the DNA damage response ascribed the inhibitory effect to a common pathway involving Chk-1, p53 and p21. Upstream of Chk-1 signal transduction depended on both ATM and ATR for all drugs except methotrexate.
We have identified critical signaling steps of the DNA damage response system activated by cytostatic drugs, which reduce the anti-tumor activity of vinca alkaloids. The obtained results encourage the development of novel therapeutic strategies to prevent pathway interactions based on the molecular understanding of drug action and drug-drug interactions.
背景/目的：蒽环类药物已被证明能够通过诱导细胞周期停滞来降低长春碱类药物的活性。本研究旨在确定信号转导的关键起始步骤，以传递对长春碱类药物细胞毒性的抑制作用。
在肿瘤细胞系和患者肿瘤细胞中，我们评估了几种新的细胞生长抑制药物类别与长春新碱一起使用。采用 RNA 干扰进行分子分析。
所有细胞生长抑制药物均观察到对长春新碱的抑制作用，诱导细胞周期停滞。DNA 损伤反应蛋白的敲低将抑制作用归因于涉及 Chk-1、p53 和 p21 的共同途径。除了甲氨蝶呤之外，Chk-1 信号转导的上游依赖于 ATM 和 ATR 对于所有药物。
我们已经确定了细胞生长抑制药物激活的 DNA 损伤反应系统的关键信号步骤，这些步骤降低了长春碱类药物的抗肿瘤活性。获得的结果鼓励根据药物作用和药物相互作用的分子理解开发新的治疗策略，以防止途径相互作用。
