5-FU is a mainstay for treating various solid tumors in adults, including digestive cancers. At bedside, treatment efficacy is often hampered by drug resistance and severe toxicities, mostly due to impaired liver detoxification related to dihydropyrimidine dehydrogenase (DPD) deficiency. We have developed a stealth liposomal formulation of 5-FU combined with two modulators (2′-deoxy-inosine and folinic acid) designed to exhibit higher antiproliferative properties while being less affected by liver uptake and subsequent DPD-related dysregulations. Lipofufol is a 100 nm diameter, pegylated liposome that proved to be stable at room temperature for at least 4 weeks. When used in vitro in the highly 5-FU-resistant human colorectal cell line SW620, mean IC50 values for standard 5-FU, 5-FU + folinic acid and LipoFufol were 29 µM, 14µM and 2µM respectively, indicative of a greater antiproliferative effect. Pharmacokinetics study was performed in rodents after I.V. administration and showed that liposomal 5-FU clearance was strongly reduced by 62% (e.g. 0.087 l/h VS. 0.231 l/h), as compared with standard 5-FU. Toxicity study was undertaken to check whether Lipofufol could be less toxic in DPD-deficient individuals, and confirmed that milder (e.g., neutrophils count: −75% VS. −96%) and shorter (e.g., 6 VS. 11 days) neutropenia was observed in DPD-deficient rats treated with liposomal 5-FU, as compared with deficient animals exposed to standard 5-FU. Tolerance studies and search for MTD were further performed in tumor-bearing mice and showed that LipoFufol could be administered safely up to 20 mg/kg I.V. on a 3QW basis for 3 consecutive weeks. In mice bearing LS174t human colorectal orthotopic xenografts, longer survival was achieved in animals treated with 20 mg/kg Lipofufol, as compared with animals treated with 80 mg/kg of standard 5-FU (e.g., 80% VS. 40% survival at 3 weeks). Overall, our data show that Lipofufol exhibits a greater anticancer efficacy both in vitro and in vivo, including in highly resistant models, with an optimized and safer pharmacokinetics profile skipping, at least in part, the DPD deficiency issue.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5490.