Relationship between Drug Release of DE-310,Macromolecular Prodrug of DX-8951f,and Gathepsins Activity in Several Tumors

摘要

DE-310 is composed of the topoisomerase-I inhibitor DX-8951 (exatecan) and carboxymethyldextran polyal-cohol (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.