In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

C98 Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively-prescribed antimetabolite, 5-FU. In this study, we tried to reverse 5-FU resistance by using a double punch strategy: combining 5-FU with a biochemical modulator to improve its tumoral activation and encapsulating both these agents in one same stealth liposome. In vitro experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a marked sensitization to 5-FU (+80%) when these cells were treated with our liposomal formulation. Results with this formulation demonstrated greater tumoral drug uptake (+30%), better activation with increased formation of active FdUMP, improved inhibition of tumor thymidylate synthase activity (-98%), and, subsequently, higher induction of early and late apoptosis. Pharmacokinetics studies performed in rats showed that higher and sustained exposure levels were achieved in animals treated with the co-encapsulated drugs. Finally, when examined in a xenograft nude mice model, our dual-agent liposomal formulation caused a 74% reduction in tumor growth with a mean doubling in survival time, whereas standard 5-FU failed to both exhibit significant antiproliferative activity and increase the lifespan of tumor-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoral activation and the use of an encapsulated formulation.