Abstract
Purpose: We compared the cytotoxic and radiosensitizing effects of gemcitabine (2′,2′-difluoro-2′-deoxycytidine, dFdCyd), a clinically valuable radiosensitizer, in colon cancer RKO cells which differed in their p53 status. The parental RKO cells, RKO-P, contain wild-type p53 protein. In RKO-E6 cells, the p53 function has been disrupted by transfection of the cells with the human papillomavirus type-16 E6 gene. Results: We found that the RKO-P cells were significantly more sensitive to dFdCyd-mediated cytotoxicity and apoptosis than RKO-E6 cells (IC10 39.3 ± 5.3 nM and 62.0 ± 6.9 nM, respectively). The cytotoxic effect of dFdCyd in RKO-P cells was accompanied by induction of the proapoptotic protein Bax at the time when p53 was induced. In contrast, similar treatment of RKO-E6 cells with dFdCyd resulted in only limited expression of Bax, suggesting that the cytotoxic effect of dFdCyd was mediated, in part, by a p53-dependent apoptosis pathway. We also studied the effect of dFdCyd on radiation sensitivity. We found that at minimally cytotoxic concentrations dFdCyd failed to radiosensitize either RKO-P or RKO-E6 cells, whereas at cytotoxic concentrations equal sensitization was produced. Finally, we assessed the influence of dFdCyd on cell cycle distribution. We found that dFdCyd synchronized RKO-P cells, whereas synchrony was not produced in p53-disrupted RKO-E6 cells. Conclusion: These results suggest that p53 status may influence dFdCyd-mediated apoptosis, cytotoxicity, and cell cycle progression but do not support an important role for p53 in radiosensitization.
Similar content being viewed by others
Author information
Authors and Affiliations
Additional information
Received: 4 May 1999 / Accepted: 19 November 1999
Rights and permissions
About this article
Cite this article
Chen, M., Hough, A. & Lawrence, T. The role of p53 in gemcitabine-mediated cytotoxicity and radiosensitization. Cancer Chemother Pharmacol 45, 369–374 (2000). https://doi.org/10.1007/s002800051004
Issue Date:
DOI: https://doi.org/10.1007/s002800051004