Antitumor activities and pharmacokinetics of silatecans DB-67 and DB-91

作者：Yeh Teng Kuang; Li Chien Ming; Chen Ching Ping; Chuu Jiuun Jye; Huang Chen Lung; Wang Hsin Sheng; Shen Chien Chang; Lee Tien Yi; Chang Chi Yen; Chang Chung Ming; Chao Yu Sheng; Lin Chin Tarng; Chang Jang Yang^*; Chen Chiung Tong

来源：Pharmacological Research, 2010, 61(2): 108-115.

DOI：10.1016/j.phrs.2009.07.005

• Camptothecin
• DB-67
• Topoisomerase I
• Anticancer activity
• Lactone stability
• Pharmacokinetics

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 94 min 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.

• 出版日期2010-2