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Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma
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2003 (English)In: Cancer Chemother Pharmacol, Vol. 52, no 5, 424-30 p.Article in journal (Refereed) Published
Abstract [en]

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/m2 (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.

Place, publisher, year, edition, pages
2003. Vol. 52, no 5, 424-30 p.
Keyword [en]
Acrylamides/*metabolism/pharmacokinetics, Aged, Antineoplastic Agents, Phytogenic/*metabolism, Camptothecin/*metabolism/pharmacokinetics, Carcinoma/drug therapy/*metabolism/surgery, Colorectal Neoplasms/drug therapy/*metabolism/surgery, Combined Modality Therapy, Drug Resistance, Neoplasm, Female, Humans, Injections, Intravenous, Male, Middle Aged, Polymers, Prodrugs/*metabolism
National Category
Basic Medicine
URN: urn:nbn:se:umu:diva-110929ISBN: 0344-5704 (Print) 0344-5704 (Linking)OAI: diva2:865855

Sarapa, Nenad Britto, Margaret R Speed, William Jannuzzo, MariaGabriella Breda, Massimo James, Christopher A Porro, MariaGrazia Rocchetti, Maurizio Wanders, Alkvin Mahteme, Haile Nygren, Peter eng Clinical Trial Clinical Trial, Phase I Germany 2003/08/09 05:00 Cancer Chemother Pharmacol. 2003 Nov;52(5):424-30. Epub 2003 Aug 6.

Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2015-10-29

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