Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma

Purpose. MAG-camptothecin (MAG-CPT) is the lead compound of a novel drug delivery system in which an active cytotoxic moiety, camptothecin (CPT), is covalently linked to a soluble polymeric carrier (MAG) to form an inactive prodrug. The mechanism of action of CPT remains unaltered, but the delivery system is thought to allow the carrier-bound drug to accumulate in tumor tissues and release the active CPT locally. This proof-of-concept clinical study was designed to determine whether MAG-CPT was preferentially delivered to or retained in tumor tissue compared to adjacent normal tissue or plasma, and to estimate the degree of intratissue release of CPT. Methods. This was an open, non-randomized study in ten adult patients scheduled for elective surgery for colorectal cancer. Patients received a single dose of 60 mg/m(2) (CPT equivalent) of MAG-CPT 24 h, 3 days or 7 days prior to surgery. Plasma, tumor, and adjacent normal tissue samples were collected simultaneously at the time of surgery and analyzed for MAG-bound and released CPT concentrations. Results. MAG-bound and free CPT concentrations in plasma, tumor, and normal tissue achieved equilibrium by 24 h after dosing, declining in parallel up to 7 days after dosing. MAG-bound CPT was delivered to similar levels to tumor and normal tissue. At 24 h after dosing, the mean+/-SD MAG-bound CPT concentrations were 861+/-216 ng/g in tumor and 751+/-215 ng/g in adjacent normal tissue, and free CPT concentrations were lower in tumor than in normal tissue (12.2+/-4.7 ng/g and 21.9+/-6.7 ng/g, respectively). At 24 h after dosing, mean+/-SD ratios of MAG-bound and free CPT in tumor and plasma were 0.13+/-0.03 and 0.22+/-0.09, respectively, and the ratios did not change for up to 7 days after dosing, indicating a lack of preferential retention of MAG-bound CPT or release of free CPT in tumor. These results are in marked contrast to previous data from animal tumor xenograft studies, where MAG-CPT levels were higher in tissue than in plasma at 3 and 7 days after a single i.v. dose. Conclusions. Delivery of CPT to the target tumor tissue is achievable by means of the MAG-CPT polymer-bound delivery system, with the equilibrium between plasma and tumor tissue concentrations of released CPT being established within 24 h after dosing. However, preferential retention of MAG-bound or released CPT in the tumor relative to normal tissue or plasma was not detected during the 7 days after dosing. The methods employed in our study could be of use in making 'go/no-go' decisions on further development of anticancer drugs.