title: Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore C™) and 5-fluorouracil.
abstract: OBJECTIVE
  To investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer.
  
  
  METHODS
  The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU.
  
  
  RESULTS
  The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg).
  
  
  CONCLUSIONS
  Single agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Hare
authors.forename: Robert W
authors.initials: RW
authors.lastname: Neijzen
authors.forename: Malathi
authors.initials: M
authors.lastname: Anantha
authors.forename: Nancy
authors.initials: N
authors.lastname: Dos Santos
authors.forename: Natashia
authors.initials: N
authors.lastname: Harasym
authors.forename: Murray S
authors.initials: MS
authors.lastname: Webb
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Dawn N
authors.initials: DN
authors.lastname: Waterhouse
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D051379:Mice; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D008081:Liposomes; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin