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

Abstract

Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (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 tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation.

Biological evaluation of MR36, a novel non-polyglutamatable thymidylate synthase inhibitor that blocks cell cycle progression in melanoma cell lines

“…Although the classical TSIs are active in a nanomolar range when polyglutamylated, and MR36-induced inhibition is insufficient in colon cancer cell lines, the results of the present study are interesting when considering that classical antifolates are not effective in melanoma cell lines. AG337 exerts stronger inhibitory activity than MR36 at the same concentrations, but AG337 is completely ineffective in melanoma cell lines [14,25]. The present study supported the evidence that melanoma cell cultures are sensitive to treatment with MR36, unlike conventional TSIs, even if the inhibitory effect is moderate.…”

An anti-EpCAM antibody EpAb2-6 for the treatment of colon cancer

“…Additionally, we have used another cancer cell line, SW620, to further demonstrate the therapeutic potential of EpAb2-6 through a double-blind experiment. SW620 is p53 mutation and less sensitive to IFL therapy [ 55 ]. The results confirmed our previous finding in that EpAb2-6 in combination with IFL had higher therapeutic efficacy at reducing tumor growth than IFL alone ( Supplementary Fig.…”

Turning cold tumors into hot tumors: harnessing the potential of tumor immunity using nanoparticles

“…For instance, liposomal 5-FU shows greater antitumor properties, both in vitro and in vivo, as compared with free 5-FU. In particular, stealth liposomal 5-FU induces deeper TS inhibition in colorectal cell lines, thus triggering Fas-mediated apoptosis because of the thymineless stress in cancer cells [35]. In a quite similar way, liposomal gemcitabine proved to perform better than standard gemcitabine in pancreatic cancer models [36], and nab-paclitaxel exhibited higher antiproliferative efficacy than free paclitaxel in a variety of solid tumors [22].…”