OncoRay - Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74/PO Box 86, 01307 Dresden, Germany.
BMC Cancer. 2010 Feb 23;10:57. doi: 10.1186/1471-2407-10-57.
Mutations within the tumor suppressor TP53 gene are one of the most common genetic alterations present at high frequency in human tumors and have been shown to be associated with resistance to radio-chemotherapy. The lack of the wild type TP53 gene in cancer cells could be exploited for therapeutic advantage using a sequence of two antagonistic drugs. The aim of this study was to selectively kill p53 deficient cells (FaDu and H1299) by taxol and to protect p53 wild type cells (A549) by the prior administration of nutlin-3 in comparison to certain known anticancer drugs (5-fluorouracil, camptothecin, roscovitine).
Cytotoxic and cytostatic properties of 5-fluorouracil, camptothecin, roscovitine and nutlin-3 administrating alone or in combination with taxol were investigated in vitro by flow cytometry.
It was found that nutlin-3 induced growth arrest and protected A549 cells from taxol. FaDu and H1299 cells responded to the same treatments with mitotic arrest and massive apoptosis. Other compounds (5-fluorouracil, camptothecin and roscovitine) revealed weaker selectivity and elevated toxicity in comparison to nutlin-3.
We propose a therapeutic strategy protecting normal cells from taxol while increasing apoptosis selectively in p53-deficient cells using nutlin-3.
抑癌基因 TP53 内的突变是人类肿瘤中高频出现的最常见的遗传改变之一，并且已经表明与放射化疗耐药性相关。癌细胞中缺乏野生型 TP53 基因，可以通过两种拮抗药物的序列来利用这一缺陷获得治疗优势。本研究的目的是通过紫杉醇选择性地杀死 p53 缺陷细胞（FaDu 和 H1299），并通过预先给予 nutlin-3 来保护 p53 野生型细胞（A549），与某些已知的抗癌药物（5-氟尿嘧啶、喜树碱、罗沙替丁）进行比较。
通过流式细胞术研究了 5-氟尿嘧啶、喜树碱、罗沙替丁和 nutlin-3 单独或联合紫杉醇的体外细胞毒性和细胞抑制作用。
发现 nutlin-3 诱导细胞生长停滞，并保护 A549 细胞免受紫杉醇的影响。FaDu 和 H1299 细胞对相同的处理产生有丝分裂停滞和大量细胞凋亡的反应。与 nutlin-3 相比，其他化合物（5-氟尿嘧啶、喜树碱和罗沙替丁）显示出较弱的选择性和更高的毒性。
我们提出了一种治疗策略，使用 nutlin-3 保护正常细胞免受紫杉醇的影响，同时选择性地增加 p53 缺陷细胞的凋亡。
