Journal
ANTI-CANCER DRUGS
Volume 22, Issue 1, Pages 24-34Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e32833f6d22
Keywords
carcinoma; cyclodextrin; 5-fluorouracil; folinic acid; toxicology
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Funding
- Southern Medical Day Care Centre
- The Illawarra Cancer Carers Inc.
- Kiama, Minnamurra and Gerringong Sunrise Rotary
- The Robert East Memorial Fund
- University of Wollongong Alumni
- NHMRC [514644]
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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 beta-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. Anti-Cancer Drugs 22:24-34 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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