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 | Moritz N Wente, Jörg Kleeff, Markus W Büchler, Jantien Wanders, Peter Cheverton, Stephen Langman, Helmut Friess |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 23
Issue 4
Pg. 339-47
(Aug 2005)
ISSN: 0167-6997 [Print] United States |
PMID | 16012793
(Publication Type: Clinical Trial, Journal Article)
|
Chemical References |
- Antineoplastic Agents, Phytogenic
- DE-310 cpd
- Delayed-Action Preparations
- Prodrugs
- Topoisomerase I Inhibitors
- exatecan
- Camptothecin
|
Topics |
- Aged
- Antineoplastic Agents, Phytogenic
(blood, pharmacokinetics)
- Area Under Curve
- Camptothecin
(administration & dosage, analogs & derivatives, blood, pharmacokinetics)
- Delayed-Action Preparations
- Humans
- Infusions, Intravenous
- Male
- Middle Aged
- Neoplasms
(chemistry, metabolism, surgery)
- Prodrugs
(administration & dosage, pharmacokinetics)
- Tissue Distribution
- Topoisomerase I Inhibitors
|