Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)
Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)
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DOI：
10.1007/s10120-016-0610-8
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发表时间：
2017-03-01
期刊：
影响因子：
7.4
通讯作者：
Ohtsu, Atsushi
中科院分区：
文献类型：
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作者：
Shitara, Kohei;Doi, Toshihiko;Ohtsu, Atsushi
癌症干细胞（CSC）具有增强的保护机制，免受氧化应激。CD 44（CD 44 v）是一种主要的CSC标志物，其变体形式显示与xCT（胱氨酸-谷氨酸转运蛋白的亚基）相互作用，该亚基维持高水平的细胞内还原型谷胱甘肽（GSH），从而保护细胞免受氧化应激。柳氮磺胺吡啶（SSZ）是一种xCT抑制剂，在体外和体内均显示可抑制CD 44 v阳性干细胞样癌细胞的存活。为了寻找能安全降低肿瘤中CD 44 v阳性细胞数量的SSZ剂量，我们对进展期胃癌患者进行了剂量递增研究，口服SSZ，每日4次，2周为1周期。在SSZ给药前和给药后14天，分别进行肿瘤活检，以评估CD 44 v的表达和肿瘤内GSH的水平。在高达12 g/天的剂量下证实了安全性，这被认为是最大耐受剂量。在8名患者的治疗前活检样本中有CD 44 v阳性细胞，其中4名患者的治疗后活检组织中CD 44 v阳性癌细胞群似乎减少。两名患者的瘤内GSH水平也下降，表明SSZ在8 g/天或更高时具有生物学有效性。这是首次研究SSZ作为靶向CSC的xCT抑制剂。在一些患者中观察到CD 44 v阳性细胞和GSH水平降低，这与SSZ在CSC中的作用模式一致。
Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted.SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH.Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater.This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.