Year-end Sale % OFF 
Abstract
PurposeTo investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer.Experimental DesignThe 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.ResultsThe 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).ConclusionsSingle 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.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer death worldwide [1,2,3]; in the United States, CRC is the third most common cause of cancer death and the third most commonly diagnosed cancer, with nearly 150,000 new cases estimated to be diagnosed in 2013 [4,5]
Pharmacokinetics/biodistribution studies demonstrated that the 5FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with Irinophore CTM (IrCTM), versus alone
Significant decreases in 5-FU elimination were observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrCTM was given intravenously
Summary
Colorectal cancer (CRC) is a leading cause of cancer death worldwide [1,2,3]; in the United States, CRC is the third most common cause of cancer death and the third most commonly diagnosed cancer, with nearly 150,000 new cases estimated to be diagnosed in 2013 [4,5]. Gut carboxylesterases (CE) generate high local concentrations of SN-38 [11,12]. This conversion can be associated with therapeutic activity, it has been linked to the intestinal damage that is responsible for much of IRI’s adverse GI toxicity [13,14,15]. IRI is entrapped in the acidic aqueous interior of the liposomes when a pH gradient is generated in the presence of the divalent metal ionophore A23187, which is required for the stability and maintenance of the pH gradient [21,26]. The combination of the ionophore-generated pH gradient, together with the presence of encapsulated Cu2+, results in excellent drug retention properties for the formulation in vivo [26,27,28]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
