DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors

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. 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. 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. 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.