Relationship between drug release of DE-310, macromolecular prodrug of DX-8951f, and cathepsins activity in several tumors

Biol Pharm Bull. 2007 Dec;30(12):2365-70. doi: 10.1248/bpb.30.2365.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Cathepsins / metabolism*
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Enzyme Inhibitors / metabolism*
  • Humans
  • Hydrolysis
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Neoplasm Transplantation
  • Neoplasms / metabolism*
  • Prodrugs / metabolism*
  • Tissue Distribution
  • Topoisomerase I Inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • DE-310 cpd
  • Enzyme Inhibitors
  • Prodrugs
  • Topoisomerase I Inhibitors
  • Cathepsins
  • exatecan
  • Camptothecin