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.

Syntheses and Evaluations of Antitumor and Antiangiogenic Compounds Conjugated with 5-Fluorouracil and Ascorbic Acid

“…5-FU, an antineoplast, is extensively used in clinical chemotherapy for the treatment of solid tumors of the gastrointestinal tract, breast, and respiratory tract. However, 5-FU has significant side-effects such as gastrointestinal toxicity [7][8][9]. Researchers have used polymer conjugates to reduce the cytotoxicity of the low molecular weight drugs by using slow release delivery [10][11][12][13][14][15][16].…”

Overcoming Resistance of Caco-2 Cells to 5-Fluorouracil through Diruthenium Complex Encapsulation in PMMA Nanoparticles

“…[Ru 2 Cl 2 (DPhF) 3 ], [Ru 2 Cl­(DPhF) 3 (O 2 CCH 3 )] ( RuA ), and 5-fluorouracil-1-acetic acid (5-FUAH) were prepared as reported elsewhere. − The other reactants and solvents were obtained from commercial sources and were used without further purification.…”

Syntheses of polyrotaxane conjugated with 5-fluorouracil and vitamins with improved antitumor activities

“…5-FUA was synthesized from 5-FU and α-chloroacetic acid as described in our previous literature ( Figure 1). 7,20 Briefly, to a solution of 5-FU (1.3 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol) in water (7.5 mL), a solution of α-chloroacetic acid (0.95 g, 10 mmol) in water (4 mL) was added and stirred at 50°C for 2 h. The pH of the reaction mixture was adjusted and kept by the addition of potassium hydroxide solution. The mixture was refluxed at 70°C for 2 h, cooled to 0°C, and acidified to pH 2 by the addition of concentrated hydrochloric acid.…”

“…Although 5-fluorouracil (5-FU) is widely used in cancer chemotherapy for the treatment of advanced breast cancer and adenocarcinomas of the gastrointestinal tract, it also has strong side effects such as diarrhea, mouth sore, poor appetite, nausea and possible occasional vomiting, gastrointestinal toxicity due to lack of selectivity on their therapeutic actions, and delivery problems. [5][6][7][8] Thus, new molecular designs and the syntheses of more potent drugs are required to develop compounds that are less toxic against normal cells and more selective against target tumors without drug resistance. 9,10 It is well known that one of the methods for the reduction of side effects is to synthesize PRs with drug molecules for drug delivery, because PR conjugate drug carrier can easily permeate into tumor and induce its passive accumulation due to the vascular leakiness and impaired lymphatic drainage in solid tumors, which is recently known as the enhanced permeability and retention (EPR) effect.…”