Treatment of Colorectal Cancer Using a Combination of Liposomal Irinotecan (Irinophore CTM) and 5-Fluorouracil

Purpose: To investigate the use of liposomal irinotecan (Irinophore CTM) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. Experimental Design: 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 CTM (IrCTM) 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 IrCTM 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 IrCTM, 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 IrCTM was given intravenously. The elimination of IrCTM was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrCTM was significantly more effective than the combination of IRI/5-FU; surprisingly, IrCTM/5-FU combinations were no more effective than IrCTM alone. The administration of combinations of 5-FU (16 mg/kg) and IrCTM (60 mg IRI/kg) showe