F10 is much more potent than 5-FU (137-314-fold depending on TP53 mutational status). 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. Rescue studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed processes. Resistance factors were derived from cell viability data and used to establish the relative potency advantage for F10. Methods: HCT-116 human CRC cells (p53 +/+) and three isogenic variants (p53 -/-, R248W/+, R248W/-) were assessed for drug response. We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil (5-FU) 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. Aim: Resistance to fluoropyrimidine drugs (FPs) is a major cause of mortality in colorectal cancer (CRC).
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