RPR‐115135, a farnesyltransferase inhibitor, increases 5‐FU‐ cytotoxicity in ten human colon cancer cell lines: Role of p53

Abstract

A new non peptidic farnesyltransferase inhibitor, RPR‐115135, in combination with 5‐FU was studied in 10 human colon cancer cell lines (HCT‐116, RKO, DLD‐1, Colo‐320, LoVo, SW‐620, HT‐29, HCT‐15, Colo‐205 and KM‐12) carrying several mutations but well characterized for p53 and Ras status. We found that there was a slight tendency (not statistically significant) for the p53 inactivated cells to be less sensitive to 5‐FU after 6 days continuous treatment. Simultaneous administration of RPR‐115135 and 5‐FU, at subtoxic concentrations, resulted in a synergistic enhancement of 5‐FU cytotoxicity in the p53 wildtype cells (HCT‐116, RKO, DLD‐1, Colo‐320, LoVo). In the p53 mutated cells (SW‐620, HT‐29, HCT‐15, Colo‐205, KM‐12) the effect was very complicated. In HCT‐15 the combination resulted in antagonism, in KM‐12 in antagonism or in synergy (at different concentrations) and in SW‐620, HT‐29 and Colo‐205 cells in synergy but only when 5‐FU was administered at high concentrations. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G2‐M arrest), as assayed by flow cytometry, only in the p53 functioning cell lines. The combination RPR‐115135 + 5‐FU increases apoptotic events only in these cell lines. In the mutated cell lines no major alterations on cell cycle arrest phenotype and no induction of apoptosis was observed. Although RPR‐115135 can potentiate the effect of 5‐FU in cells in which p53 function is disrupted, these data suggest strongly that RPR‐115135 significantly enhances the efficacy of 5‐FU only when p53 is functioning.