新規水溶性カンプトテシン誘導体、SN38-BGLによる、ヒト肺がん細胞移植モデルマウスにおける抗腫瘍効果と副作用の解析

• Published in: 日本薬理学会年会要旨集 p. 3-B-O14-3
• Main Authors: 宮本, 理人, 土橋, 有希, 阿部, 真治, 和泉, 俊尋, 秦野, 彩, 今西, 正樹, 池田, 康将, 土屋, 浩一郎
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_3-B-O14-3

Camptothecin derivatives, such as CPT-11 (irinotecan), possess potent antitumor properties but are often hampered by their hydrophobic nature, leading to severe diarrhea as a common adverse effect. To address this challenge, we designed and synthesized novel highly hydrophilic camptothecin derivatives by conjugating SN38 with branched glycerol trimer (SN38-BGL). This unique strategy aimed to enhance the therapeutic benefits while minimizing the adverse effects. In murine xenograft models of human lung cancer, SN38-BGLs exhibited comparable or slightly superior tumor-suppressing efficacy compared to CPT-11 without the onset of early or late diarrhea. Additionally, histological analysis revealed that SN38-BGL treatment resulted in longer villi in the jejunum and ileum compared to CPT-11, indicating that SN38-BGL is less harmful. Digestion by liver microsome ex vivo did not yield SN38 but a few other molecules, suggesting possible involvement of other active metabolites than SN38. Our findings suggest that SN38-BGLs represent a promising class of hydrophilic camptothecin derivatives with the potential to mitigate severe diarrhea while maintaining antitumor efficacy, offering new prospects for pharmacological interventions.