Abstract：
: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.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Yeh TK,Li CM,Chen CP,Chuu JJ,Huang CL,Wang HS,Shen CC,Lee TY,Chang CY,Chang CM,Chao YS,Lin CT,Chang JY,Chen CTdoi
10.1016/j.phrs.2009.07.005subject
Has Abstractpub_date
2010-02-01 00:00:00pages
108-15issue
2eissn
1043-6618issn
1096-1186pii
S1043-6618(09)00190-Xjournal_volume
61pub_type
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