Hashimoto Yosuke, Yagi Kiyohito, Kondoh Masuo
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan.
Pflugers Arch. 2017 Jan;469(1):45-53. doi: 10.1007/s00424-016-1878-6. Epub 2016 Sep 15.
Given that most malignant tumors are derived from epithelium, developing a strategy for treatment of epithelium-derived cancers (i.e., carcinomas) is a pivotal issue in cancer therapy. Carcinomas, including ovarian, breast, prostate, and pancreatic cancers, are known to overexpress various claudins (CLDNs); in particular, CLDN-3 and -4 are frequently overexpressed in malignant case. The generation of CLDN binders is a key for expanding CLDN-targeted cancer therapy but has been delayed due to the small size of CLDN extracellular domains (approximately 50 amino acids for the first domain and 15 amino acids for the second) and their high homology among species. Interestingly, however, the receptors for Clostridium perfringens enterotoxin (CPE), a foodborne toxin in humans, happen to be identical to CLDN-3 and -4. Thus, the first CLDN binder, CPE, has provided us CLDN-targeted cancer therapy from a concept into a potential reality. In this review, we describe roles of CPE technology in cancer therapy and discuss future directions in the CLDN-targeting concept-to-therapy process.
鉴于大多数恶性肿瘤起源于上皮组织，开发一种治疗上皮组织来源癌症（即癌）的策略是癌症治疗中的关键问题。已知包括卵巢癌、乳腺癌、前列腺癌和胰腺癌在内的癌会过度表达各种紧密连接蛋白（CLDNs）；特别是，CLDN-3和-4在恶性病例中经常过度表达。生成CLDN结合剂是扩大CLDN靶向癌症治疗的关键，但由于CLDN细胞外结构域尺寸小（第一个结构域约50个氨基酸，第二个结构域约15个氨基酸）以及它们在物种间的高度同源性，这一进展一直滞后。然而，有趣的是，产气荚膜梭菌肠毒素（CPE）（一种人类食源毒素）的受体恰好与CLDN-3和-4相同。因此，首个CLDN结合剂CPE已使我们从概念上实现CLDN靶向癌症治疗成为了潜在的现实。在本综述中，我们描述了CPE技术在癌症治疗中的作用，并讨论了CLDN靶向从概念到治疗过程的未来方向。
