Preclinical evaluation of novel, all-in-one formulations of 5-fluorouracil and folinic acid with reduced toxicity profiles.

Abstract

5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations such as phlebitis and catheter blockages persist with the administration of these drugs in combination, and are associated with reduced efficacy and/or quality of life for patients. We have reported earlier on the novel, all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating β-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid. We carried out toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared with 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared with the dose-matched sequential administration of 5-FU:folinic acid. Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by the tissue distribution and pharmacokinetic studies of 5-FU, but was generally better tolerated as determined by weight loss, hematological, and other clinical parameters. Compared with 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, using human carcinoma tumor models in mice, Fluorodex resulted in equivalent or improved efficacy profiles compared with 5-FU:folinic acid. In conclusion, these novel, all-in-one formulations represent a superior injectable form of 5-FU that allows codelivery of folinic acid. This should translate into improved patient tolerability with potential for enhanced efficacy.

• Authors: Tamantha K Stutchbury, Kara L Vine, Julie M Locke, Jeremy S Chrisp, John B Bremner, Philip R Clingan, Marie Ranson
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 22 Issue 1 Pg. 24-34 (Jan 2011) ISSN: 1473-5741 [Electronic] England
• PMID: 20881836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• beta-Cyclodextrins
• Leucovorin
• Fluorouracil

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Screening Assays, Antitumor
• Female
• Fluorouracil (administration & dosage, adverse effects, pharmacokinetics)
• HCT116 Cells
• HT29 Cells
• Humans
• Leucovorin (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Rabbits
• Rats
• Tissue Distribution
• Xenograft Model Antitumor Assays
• beta-Cyclodextrins (administration & dosage, chemistry)