Division of Gastroenterology, Infectiology, Rheumatology, Clinical Physiology/Nutritional Medicine, Medical Department, Charitè - Universitätsmedizin Berlin, Berlin, Germany.
Division of Cell and Developmental Biology, Institute of Biology, University of Leipzig, Leipzig, Germany.
Methods Mol Biol. 2022;2521:173-188. doi: 10.1007/978-1-0716-2441-8_9.
Bacterial toxins gain growing attention as potential cancer treatment due to their potent cytotoxic effects. Among the very different toxins with diverse modes of action, the Clostridium perfringens enterotoxin (CPE) is in focus to treat solid cancers. This toxin targets the tight junction proteins claudin-3 and -4 (Cldn-3/4), which are frequently overexpressed in solid cancers. Binding to these claudins induces pore formation in the host cell plasma membrane leading to rapid oncoleaking cell death of tumor cells. Based on this, extending the targeting of CPE beyond Cldn-3/4 is of interest, since other claudins, such as claudin-1 or -5 are often overexpressed in various cancer entities such as non-small-cell lung cancer (NSCLC) or papillary thyroid carcinoma. In this chapter we describe the modification of a CPE-encoding vector by structure-directed mutagenesis to either preferentially target Cldn-1 and -5 or to expand targeting to Cldn1-9 for improved broadened cytotoxic targeting of claudin-overexpressing tumors such as but not limited to lung cancer via CPE gene transfer.
由于细菌毒素具有很强的细胞毒性作用，它们作为潜在的癌症治疗方法越来越受到关注。在具有不同作用模式的非常不同的毒素中，产气荚膜梭菌肠毒素（CPE）是治疗实体瘤的焦点。这种毒素靶向紧密连接蛋白 Claudin-3 和 -4（Cldn-3/4），这些蛋白在实体瘤中经常过表达。与这些 Claudin 结合会在宿主细胞膜的质膜中诱导孔形成，导致肿瘤细胞的快速溶瘤性死亡。基于此，将 CPE 的靶向作用扩展到 Cldn-3/4 之外是很有意义的，因为其他 Claudin 蛋白，如 Claudin-1 或 -5，在各种癌症实体中经常过表达，如非小细胞肺癌（NSCLC）或甲状腺乳头状癌。在本章中，我们描述了通过结构导向诱变对 CPE 编码载体进行修饰，以优先靶向 Claudin-1 和 -5，或扩大靶向 Claudin1-9 的范围，以通过 CPE 基因转移改善针对 Claudin 过表达肿瘤的广泛细胞毒性靶向，例如但不限于肺癌。
