title: 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.affiliation: School of Biological Sciences, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Tamantha K
authors.initials: TK
authors.lastname: Stutchbury
authors.forename: Kara L
authors.initials: KL
authors.lastname: Vine
authors.forename: Julie M
authors.initials: JM
authors.lastname: Locke
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Chrisp
authors.forename: John B
authors.initials: JB
authors.lastname: Bremner
authors.forename: Philip R
authors.initials: PR
authors.lastname: Clingan
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D004338:Drug Combinations; D047392:beta-Cyclodextrins; D002955:Leucovorin; D005472:Fluorouracil