Role of p53 status in combination effect of chemotherapeutic agents and radiation

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Purpose : Topoisomerase inhibitots including camptothecin are being studied as potential radiosensitizers. CPT-11 is a derivative of camptothecin and is clinically available. We investigated here the effects of SN-38 (an active metabolite of CPT-11) on 4 unirradiated and irradiated murine fibroblast cell lines, with different statuses of p53, to clarify the role of p53 in the radiosensitizing activity of SN-38.Materials and Methods : Four fibroblast cell lines, MT158, MT158/neo, MT158/wtp53 and MT158/mp53 with the same genetic background but with different p53 statuses, were used. Exponentially growing cells were treated with SN-38 (200nM) and incubated with the drug for 30 min. Cells were then irradiated (0 to 12 Gy), and further incubated with the drug for 2h. The cell survival rate was determined using a conventional clonogenic assay. The effects of the treatments on the cell cycle were analyzed with flowcytometric assay. Apoptosis after these treatments was also detected by an Annexin V assay.Results : There were no significant differences in sensitivity to radiation or treatment of SN-38 among these cell lines. The combined treatment of irradiation and SN-38 showed supraadditive effects in all 4 cell lines independent of their p Transient arrest in G2 with a decreased percentage of cells in both the S and G1 phases was observed 8 h after treatment with either SN-38 alone, irradiation or their combination, regardless of the p53 status. No significant differences in frequency of apoptosis was observed between treatment and control groups in two cell lines with or without wild type p53.Conclusion : The combination of irradiation and treatment of SN-38 showed supraadditive effects in all 4 cell lines tested here, and the status of p53 did not play a role in the combination effect.