title: DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors.
abstract: BACKGROUND
  DE-310 is composed of the topoisomerase-I-inhibitor DX-8951 (exatecan) and a biodegradable macromolecular carrier, which are covalently linked by a peptidyl spacer. In pre-clinical studies, high levels and prolonged retention of conjugated DX-8951 (carrier-bound DX-8951) have been observed in tumor tissues following DE-310 administration. This phenomenon is explained as the enhanced permeability and retention (EPR) effect. DX-8951 and G-DX-8951 (glycyl-DX-8951) exerting anti-tumor activity in vivo are released from DE-310 by enzymatic cleavage of the spacer.
  
  
  METHODS
  To quantify the concentration of conjugated DX-8951, DX-8951 and G-DX-8951 in human tissues, six patients with different solid tumor types received 6.0 mg/m(2) of DE-310 (as equivalent of DX-8951) as a single three-hour infusion administered 7 days (+/-2 days) prior to scheduled tumor resection. Drug concentrations were then determined in the resected tissues. To evaluate the plasma PK of DE-310, plasma samples were taken up to 42 days post dosing.
  
  
  RESULTS
  There were no severe side effects of the DE-310 infusion. Concentrations of conjugated DX-8951, DX-8951 and G-DX-8951 were in general similar in tumor and relevant normal tissue samples and preferential accumulation of DE-310, DX-8951 and G-DX-8951 in human tumor tissues was not observed.
  
  
  CONCLUSIONS
  These data indicate that there is distribution of DE-310 into tissue and that DX-8951 and G-DX-8951 are released slowly over an extended period from DE-310 providing prolonged exposure similar to a continuous infusion. However, the similarity in the concentrations in tumor and relevant normal tissues does not support the EPR concept in the studied human cancers.
authors: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Moritz N
authors: MN
authors: Wente
authors: Jörg
authors: J
authors: Kleeff
authors: Markus W
authors: MW
authors: Büchler
authors: Jantien
authors: J
authors: Wanders
authors: Peter
authors: P
authors: Cheverton
authors: Stephen
authors: S
authors: Langman
authors: Helmut
authors: H
authors: Friess
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000601:surgery; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C452060:DE-310 cpd; D003692:Delayed-Action Preparations; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; C095887:exatecan; D002166:Camptothecin