Cytotoxicity and Anticancer Activity of Macromolecular Prodrugs of 5-Fluorouracil

Abstract

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.