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

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.

Formulation and Pharmacokinetics of Thermosensitive Stealth® Liposomes Encapsulating 5-Fluorouracil

“…Hence, 40 mM lipid initial concentration appears to be an optimum between good encapsulation and excipient cost. Passive encapsulation allows to yield a 5-FU concentration of up to 3.6 mg 5-FU/mL compatible with an efficient treatment in vivo on HT-29 xenograft tumors in mice (injection of 20-40 mg 5-FU/kg) (17,32). These results are in agreement with literature, where similar encapsulation efficacy of 5-FU has been reported for DPPC liposomes (14).…”

Irinophore C™, a lipid nanoparticulate formulation of irinotecan, improves vascular function, increases the delivery of sequentially administered 5-FU in HT-29 tumors, and controls tumor growth in patient derived xenografts of colon cancer

“…The data show that any therapeutic potential of the combination is compromised by an unexpected increase in toxicity [22]. The reasons for the enhanced toxicity are not well-understood although it may be due to IrC™ treatment prolonging the circulation lifetime of 5-FU [22]. The observed improvements in tumor perfusion following IrC™ treatment [20,21,23] suggest the possibility that combination treatments with IrC™ and 5-FU might be more efficacious if 5-FU was administered after IrC™ treatment in a sequential, rather than concurrent, manner.…”

“…Recognizing that IrC™, if approved for clinical use, will be used in combination with other drugs, our research team has examined the therapeutic effects when IrC™ and 5-FU are administered concurrently [22]. The data show that any therapeutic potential of the combination is compromised by an unexpected increase in toxicity [22].…”

“…The data show that any therapeutic potential of the combination is compromised by an unexpected increase in toxicity [22]. The reasons for the enhanced toxicity are not well-understood although it may be due to IrC™ treatment prolonging the circulation lifetime of 5-FU [22].…”

New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway

“…The primary method currently used to treat all stages of colon cancer is surgery. After tumor excision, chemotherapeutic drugs, such as irinotecan (CPT-11), 5-fluorouracil (5-FU), and oxaliplatin, are typically used to further eradicate any residual tumor cells [2,3] . However, in the majority of cancer patients, currently available chemotherapies have had only partial success, owing to chemoresistance and side effects [4] .…”