Relationship between drug release of DE-310, macromolecular prodrug of DX-8951f, and cathepsins activity in several tumors.
DE-310 is composed of the topoisomerase-I inhibitor DX-8951 (exatecan) and carboxymethyldextran polyalcohol (CM-Dex-PA) carrier, which are covalently linked via peptidyl spacer (Gly-Gly-Phe-Gly). In this study, we investigated relationship between the cathepsin activity and the drug release of DE-310 by use of human liver origin cathepsin (B, L and H) and tumor cells (murine tumor cells (Meth A and M5076), and human tumor cells (HCT116, A549, PC-12, T98G, and HL-60)). Preliminary studies indicated that human liver cathepsin B produced Glycyl DX-8951 (G-DX-8951) from DE-310 more preferentially than DX-8951, whereas human liver cathepsin L produced DX-8951 preferentially. Release of drugs from DE-310 and cathepsin activities were measured in tumor cell types. The release of both DX-8951 and G-DX-8951 from DE-310 correlated well with cathepsin B activity of tumor cells. The release of DX-8951 was weakly, but not significantly, correlated with cathepsin L activity. In M5076 (high cathepsin activity) or Meth A (low cathepsin activity) xenograft models, the levels of DX-8951 and G-DX-8951 in M5076 were higher than in Meth A after single intravenous administration of DE-310. Our findings suggest that cathepsin B is primarily responsible for drug release from DE-310 in tumor.
Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., Kasai R&D Center, 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. shiose.yoshinobu.gn@daiichisankyo.co.jp
Yoshinobu
Y
Shiose
Yusuke
Y
Ochi
Hiroshi
H
Kuga
Fumiyoshi
F
Yamashita
Mitsuru
M
Hashida
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C452060:DE-310 cpd; D004791:Enzyme Inhibitors; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D002403:Cathepsins; C095887:exatecan; D002166:Camptothecin