使用Tg-rasH2小鼠的超短期两阶段皮肤致癌试验评估TRPV1拮抗剂motugivatrep（SJP-0132）的皮肤致癌性

摘要(中文译文)

莫图伐瑞普（Motugivatrep，SJP-0132）是一种瞬时受体电位阳离子通道V亚家族成员1（TRPV1）拮抗剂，目前正被开发为治疗干眼症的眼科药物。由于TRPV1拮抗剂在皮肤致癌作用中的角色仍存在争议，本研究旨在利用Tg-rasH2小鼠的超短期两阶段皮肤致癌模型，探讨莫图伐瑞普是否促进皮肤肿瘤发生。在以7,12-二甲基苯并[a]蒽单次皮肤涂抹启动后，将莫图伐瑞普以0、150、300或750 µg/50 µL/只的剂量每日一次局部涂抹于小鼠皮肤，持续7周。阳性对照组每周接受一次12-O-十四烷酰佛波醇-13-乙酸酯（TPA）处理。在接受莫图伐瑞普处理的所有动物中，均未观察到皮肤肿瘤或癌前病变。相比之下，TPA处理显著增加了皮肤肿瘤的形成，证实了该检测方法的有效性。这些结果表明，莫图伐瑞普在该Tg-rasH2小鼠模型中缺乏皮肤肿瘤促进活性，为莫图伐瑞普的皮肤暴露提供了安全性信息。

Abstract

Motugivatrep (SJP-0132), a transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonist, is being developed as an ophthalmic drug for dry eye disease. Since the role of TRPV1 antagonists in skin carcinogenesis remains controversial, this study aimed to investigate whether motugivatrep promotes skin tumorigenesis using an ultra-short-term two-stage skin carcinogenesis model with Tg-rasH2 mice. Following initiation with a single dermal application of 7,12-dimethylbenz[]anthracene, motugivatrep was applied topically at doses of 0, 150, 300, or 750 µg/50 µL/animal once a day to mouse skin for 7 weeks. The positive control group received 12--tetradecanoylphorbol-13-acetate (TPA) once weekly. No skin tumors or preneoplastic lesions were observed in any animals treated with motugivatrep. In contrast, treatment with TPA significantly increased skin tumor formation, confirming the validity of the assay. These results indicated that motugivatrep lacked skin tumor promotion activity in this Tg-rasH2 mice model, providing safety information regarding dermal exposure to motugivatrep.

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