Cell Res:科学家揭示喜树碱类药物肠道毒性机制和克服毒性治疗方案

2017-04-17 佚名 上海药物研究所

喜树碱类药物是细胞毒类药物的重要代表,也是当前临床使用最为广泛的一类细胞毒类药物,在肿瘤临床治疗中占有不可替代的重要地位。中国科学院上海药物研究所多年来致力于喜树碱类药物的抗肿瘤新药研发,自主研发的喜树碱类候选新药希明替康目前正在进行临床 Ib 期研究。已经完成的临床 Ia 期试验显示,希明替康人体耐受性好、安全性高、低剂量显效、安全窗口广,显示出极富潜质的应用前景。然而,与其它的细胞毒类药物一样

喜树碱类药物是细胞毒类药物的重要代表,也是当前临床使用最为广泛的一类细胞毒类药物,在肿瘤临床治疗中占有不可替代的重要地位。中国科学院上海药物研究所多年来致力于喜树碱类药物的抗肿瘤新药研发,自主研发的喜树碱类候选新药希明替康目前正在进行临床 Ib 期研究。已经完成的临床 Ia 期试验显示,希明替康人体耐受性好、安全性高、低剂量显效、安全窗口广,显示出极富潜质的应用前景。然而,与其它的细胞毒类药物一样,喜树碱类药物严重的毒性问题极大地制约了其临床应用。其中,迟发性腹泻是喜树碱类药物最严重的毒性反应,临床发生率高达 40%,且个体差异大,严重者可致患者死亡。一直以来,因机制不明,目前在临床上仅能在腹泻发生之后采用对症治疗的手段,收效甚微,严重制约药物临床获益。

针对上述问题,上海药物所肿瘤药理团队在大力推进自主新药研发的同时,与中科院上海生命科学研究院研究员孙兵课题组合作,开展了喜树碱类药物的毒性机制研究,旨在为喜树碱类药物的个性化治疗提供依据。研究发现喜树碱类药物能引起肠道上皮细胞释放双链 DNA(dsDNA),后者被外泌体携带(exosome)进入微环境的固有免疫细胞,激活 AIM2 介导的炎症小体反应,导致肠道局部炎性损伤,是喜树碱类药物所致腹泻的核心机制。基于该机制,研究采用临床样本证实 dsDNA 是喜树碱类药物的毒性标志物。该研究首次揭示喜树碱毒性机制,发现喜树碱类药物的毒性标志物和缓解毒性发生的联合用药方案,为临床规避毒性发生,增加临床获益提供理论依据,也为细胞毒类药物的个性化治疗提供重要的理论依据。

该研究工作于4月14日在线发表在国际期刊《细胞研究》(Cell Research)上。研究得到了中科院战略性先导科技 A 类专项“个性化药物——基于疾病分子分型的普惠新药研发”的支持,以及国家自然科学基金委和科技部有关项目的资助。

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