Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
Pharmacol Res. 2010 Feb;61(2):108-15. doi: 10.1016/j.phrs.2009.07.005. Epub 2009 Jul 28.
DB-67 and its lactone homolog DB-91 are derivatives of topoisomerase I inhibitor camptothecin (CPT) with silyl moiety, which may exhibit a slower inactivation process by changed kinetics of protein binding and/or hydrolysis of its lactone ring and result in increased antitumor activity and decreased toxicity. Pharmacokinetic properties and antitumor activities of the two silatecans were studied and compared. The lactone ring of DB-91 is more stable than those of all the other CPT derivatives in mouse plasma. Both silatecans were metabolized faster than CPT in mouse and human liver microsomes. Pharmacokinetic study revealed a plasma elimination half-life (t(1/2)) of 33 and 94min for DB-67 and DB-91, respectively; similar systemic exposure in plasma between DB-67 and DB-91; and similar volume of distribution at the steady state between DB-67 and DB-91, approximately 15-fold smaller than that of CPT. While DB-91 showed limited activities, DB-67 exhibited activities against the growth of in vivo-like histocultured human tumors and s.c. xenografted human tumors in nude mice. In conclusion, DB-67 is more effective, compared to DB-91, against human tumor growth in in vitro, in vivo-like and in vivo systems. Further pre-clinical and clinical investigations of DB-67 are warranted.
DB-67 和它的内酯同系物 DB-91 是拓扑异构酶 I 抑制剂喜树碱 (CPT) 的硅烷衍生物，由于蛋白结合动力学的改变和/或内酯环水解的变化，可能表现出较慢的失活过程，从而导致抗肿瘤活性增加和毒性降低。研究并比较了这两种硅烷类药物的药代动力学特性和抗肿瘤活性。DB-91 的内酯环在小鼠血浆中比所有其他 CPT 衍生物都更稳定。两种硅烷类药物在小鼠和人肝微粒体中的代谢速度都比 CPT 快。药代动力学研究显示，DB-67 和 DB-91 的血浆消除半衰期（t(1/2)）分别为 33 和 94min；DB-67 和 DB-91 在血浆中的系统暴露相似；DB-67 和 DB-91 的稳态分布容积相似，约为 CPT 的 15 倍。虽然 DB-91 表现出有限的活性，但 DB-67 对体内样组织培养的人肿瘤和裸鼠皮下异种移植的人肿瘤的生长表现出活性。总之，与 DB-91 相比，DB-67 在体外、体内样和体内系统中对人肿瘤生长的效果更显著。需要进一步对 DB-67 进行临床前和临床研究。
