Aim: Resistance to fluoropyrimidine drugs (FPs) is a major cause of mortality in colorectal cancer (CRC). We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil (5FU) in four human CRC cell lines that differ only in TP53 mutational status to determine how p53 mutations affect drug response and whether F10 is likely to improve outcomes.
Methods: HCT-116 human CRC cells (p53+/+) and three isogenic variants (p53-/-, R248W/+, R248W/-) were assessed for drug response. Resistance factors were derived from cell viability data and used to establish the relative potency advantage for F10. Rescue studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed processes.
Results: Significant resistance to 5-FU resulted from p53-loss or from gain-of-function (GOF) mutation (R248W) and was greatest when GOF mutation was coupled with loss of wild-type p53. F10 is much more potent than 5-FU (137-314-fold depending on TP53 mutational status). F10 and 5-FU induce apoptosis by DNA- and RNA-directed mechanisms, respectively, and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with leucovorin.
Conclusion: TP53 mutational status affects inherent sensitivity to FPs, with p53 GOF mutations most deleterious. F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due, in part, to TP53 mutations.6,7.
Keywords: Fluoropyrimidine; colorectal cancer; drug resistance; p53.