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

Abstract

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.

• Authors: Nenad Sarapa, Margaret R Britto, William Speed, MariaGabriella Jannuzzo, Massimo Breda, Christopher A James, MariaGrazia Porro, Maurizio Rocchetti, Alkvin Wanders, Haile Mahteme, Peter Nygren
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 52 Issue 5 Pg. 424-30 (Nov 2003) ISSN: 0344-5704 [Print] Germany
• PMID: 12904897 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Acrylamides
• Antineoplastic Agents, Phytogenic
• Polymers
• Prodrugs
• poly(1-methacryloylamido-2-hydroxypropane-co-20-O-(methacryloylglycyl-6-aminohexanoylglycyl))
• Camptothecin

Topics

• 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)