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Cytotoxicity and Anticancer Activity of Macromolecular Prodrugs of 5-Fluorouracil

Department of Organic Chemistry, Polymer Materials Research Group, University of Ghent, Krijgslaan 281 S4 bis, B-9000 Ghent, Belgium

Etienne H. Schacht

Department of Organic Chemistry, Polymer Materials Research Group, University of Ghent, Krijgslaan 281 S4 bis, B-9000 Ghent, Belgium

Leonard W. Seymour

CRC Institute for Cancer Studies, University of Birmingham, United Kingdom

Dave Anderson

CRC Institute for Cancer Studies, University of Birmingham, United Kingdom

Mahmood Shoaibi

CRC Institute for Cancer Studies, University of Birmingham, United Kingdom

Polymeric conjugates of 5-fluorouracil (5-FU) were synthesized by covalent attachment of tetrapeptide chains with 2-(5-fluorouracil-1-yl)glycine ethyl ester [Gly(FU)OEt] as the C-terminus, to poly(ethylene glycol) (PEG) and dextran (Dex). Cytotoxicity of these conjugates was compared with free 5-FU against the murine colorectal carcinoma cell line C26. All the conjugates displayed lower cytotoxicity than 5-FU. The chemical structure and the configuration of the tetrapeptide chains influenced the activity of the conjugates. Materials containing the tetrapeptide Gly-Phe-Gly-Gly(FU)OEt (l,d), with Dex-based conjugates were more cytotoxic than the analogue PEG-based conjugate. PEG-Gly-Phe-Gly-Gly(FU)OEt (l,d) administered to mice at doses of 150 and 250 mg 5-FU equivalent/kg, following by inoculation of C26 tumor cells, mediated much less toxicity than equivalent doses of free 5-FU. The anticancer activity achieved using free and polymer-bound drugs were comparable, although decreased toxicity of the conjugate should facilitate administration of increased doses with improved efficacy.

Journal of Bioactive and Compatible Polymers, Vol. 12, No. 4, 265-281 (1997)
DOI: 10.1177/088391159701200401


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