Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors(Biopharmacy)
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概要
- 論文の詳細を見る
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.
- 2007-12-01
著者
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Yamashita Fumiyoshi
Department Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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Hashida Mitsuru
Department Of Basic Pharmaceutics Faculty Of Pharmaceutical Sciences Kyoto University
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SHIOSE Yoshinobu
Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., Kasai R&D Center
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OCHI Yusuke
R&D Planning Department, Planning Group, Daiichi Sankyo Co., Ltd.
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KUGA Hiroshi
Development Research Department, Daiichi Sankyo Inc.
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Ochi Yusuke
R&d Planning Department Planning Group Daiichi Sankyo Co. Ltd.
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Kuga Hiroshi
Development Research Department Daiichi Sankyo Inc.
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Shiose Yoshinobu
Biological Research Laboratories Iv Daiichi Sankyo Co. Ltd. Kasai R&d Center
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