State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, PR China.
Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, PR China.
Bioorg Med Chem Lett. 2023 Feb 1;81:129128. doi: 10.1016/j.bmcl.2023.129128. Epub 2023 Jan 10.
7-Ethyl-10-hydroxycamptothecin (SN38), the bioactive metabolite of irinotecan (CPT-11), has been shown to be 100-1000 times more effective than CPT-11. However, the poor water solubility and bioavailability of SN38 constrained its clinical application. In this study, we synthesized a novel SN38-glucose conjugate (FSY04) to address this issue. Our in vitro studies indicated that FSY04 had a potent inhibitory ability against colorectal cancer (CRC) cell lines of SW-480 and HCT-116 compared to the inhibitory capacity of CPT-11. Interestingly, FSY04 possessed lower cytotoxicity against normal cell lines of LO2 and 293T in contrast with CPT-11. Moreover, FSY04 is more active than CPT-11 in inducing apoptosis, inhibiting migration, and invasion. In vivo experiments suggested that half of the equivalent of FSY04 inhibited the growth of SW480 in the xenograft tumor model better than one equivalent of CPT-11. Our data demonstrated FSY04 to be a promising agent in CRC therapy.
7-乙基-10-羟基喜树碱（SN38）是伊立替康（CPT-11）的生物活性代谢物，其活性比 CPT-11 强 100-1000 倍。然而，SN38 的水溶性和生物利用度差限制了其临床应用。在本研究中，我们合成了一种新型 SN38-葡萄糖缀合物（FSY04）来解决这个问题。我们的体外研究表明，FSY04 对 SW-480 和 HCT-116 等结直肠癌细胞系的抑制能力强于 CPT-11。有趣的是，与 CPT-11 相比，FSY04 对 LO2 和 293T 等正常细胞系的细胞毒性较低。此外，FSY04 在诱导细胞凋亡、抑制迁移和侵袭方面比 CPT-11 更有效。体内实验表明，在异种移植肿瘤模型中，FSY04 的一半等效物抑制 SW480 生长的效果优于 CPT-11 的一个等效物。我们的数据表明 FSY04 是结直肠癌治疗的一种有前途的药物。
