Antitumor activities and pharmacokinetics of silatecans DB-67 and DB-91
Journal
Pharmacological Research
Journal Volume
61
Journal Issue
2
Pages
108-115
Date Issued
2010
Author(s)
Yeh T.-K.
Li C.-M.
Chen C.-P.
Chuu J.-J.
Huang C.-L.
Wang H.-S.
Shen C.-C.
Lee T.-Y.
Chang C.-Y.
Chang C.-M.
Chao Y.-S.
Chang J.-Y.
Chen C.-T.
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 (t1/2) 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. ? 2009 Elsevier Ltd. All rights reserved.
Subjects
Anticancer activity; Camptothecin; DB-67; Lactone stability; Pharmacokinetics; Topoisomerase I
SDGs
Other Subjects
camptothecin; camptothecin derivative; db 67; db 91; DNA topoisomerase; DNA topoisomerase inhibitor; lactone; silatecan derivative; unclassified drug; animal cell; animal experiment; animal model; animal tissue; antineoplastic activity; article; bolus injection; cancer inhibition; clinical effectiveness; controlled study; drug distribution; drug efficacy; drug elimination; drug half life; drug metabolism; drug stability; drug structure; human; human cell; in vitro study; in vivo study; liver microsome; male; malignant neoplastic disease; mouse; nonhuman; nude mouse; priority journal; steady state; structure activity relation; tumor xenograft; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; DNA Topoisomerases, Type I, Eukaryotic; Drug Resistance, Neoplasm; Drug Stability; Enzyme Inhibitors; Female; Half-Life; Humans; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver; Neoplasms; Organosilicon Compounds; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays
Type
journal article