Influence of resistance to 5-fluorouracil and tomudex on [18F]‑FDG incorporation, glucose transport and hexokinase activity

Drug resistance is a major obstacle to cancer cure and may influence [18F]-fluorodeoxyglucose (FDG) incorporation. In this study, glucose transport, hexokinase activity and [18F]-FDG incorporation were measured in drug-resistant tumour cells generated by exposing H630 colon and MCF7 breast cancer cells to increasing concentrations of tomudex (raltitrexed) or 5-fluorouracil (5FU). Drug sensitivity was determined using the XTT assay: Tomudex-resistant (H630TDX and MCF7TDX) cells were more than 40,000-fold less sensitive to tomudex than were the parental wild-type, H630WT and MCF7WT cells, respectively. 5FU-resistant (H630R10) cells were 100-fold less sensitive than parental H630WT cells to 5FU. As previously reported for 5FU-resistant MCF7 breast cancer cells, [18F]-FDG incorporation was decreased in H630R10 colon cancer cells compared to the parental line. By contrast, both tomudex-resistant cell lines exhibited increased [18F]-FDG incorporation compared with the parental lines. H630R10 and MCF7TDX cells exhibited higher rates of glucose transport, measured as the initial rate of O-methyl-glucose (OMG) uptake, compared to wild-type cells; however, glucose transport was not significantly different between H630TDX cells and the parental cells. Hexokinase activity was lower in H630R10 and MCF7TDX cells compared with sensitive parental cells but unchanged in H630TDX cells. In conclusion, our results show that [18F]-FDG incorporation is influenced by resistance to antifolate and fluoropyrimidine-based anti-cancer drugs in a drug-dependent manner and the underlying mechanisms appear to be cell- and drug-dependent. Glucose transport may be a useful marker of resistance to 5FU.