Effect of pentoxifylline on radiation-induced G2-phase delay and radiosensitivity of human colon and cervical cancer cells

Cells of three adherent cell lines with mutated p53 (WiDr and C33-A) and disrupted p53 (C4-I) were used to investigate the effect of pentoxifylline (PTX) on radiation-induced G2-phase block and its relationship to radiosensitivity. Postirradiation exposure to 0.25-1.0 mM PTX resulted in an increase in radiosensitivity in a concentration-dependent manner as determined by a clonogenic assay. The change in radiation sensitivity was quantified by calculating the enhancement ratio (ER) at a clinically relevant dose of 2 Gy; the ER for WiDr cells was 1.23+/-0.03 and 1.39+/-0.15 for 0.5 and 1.0 mM PTX, respectively. For C33-A cells, the ER ranged from 1.04+/-0.04 to 1.99+/-0.17 for 0.25-1.0 mM PTX, whereas for C4-I cells the values were 1.29+/-0.04 and 1.76+/-0.17 for 0.25 and 0.5 mM PTX. In asynchronous WiDr, C33-A and C4-I cells, flow cytometry analysis showed a dose-dependent accumulation of cells in G2/M phase which was detectable at 6 h and peaked at 12 h after irradiation. Such a G2/M-phase block was transient at a dose of 2 Gy and persisted at 48 or 72 h after a dose of 4 or 6 Gy. At 12 h after 2 Gy, PTX significantly reduced the radiation-induced G2/M-phase block in a dose-dependent manner. After the higher doses of 4 and 6 Gy, the dose-dependent G2-phase arrest was significantly alleviated at 24 h by treatment with PTX, and the kinetics of this alleviation depended on the radiation dose. The results demonstrate that human colon and cervical cancer cells characterized by a mutated or disrupted p53 (i.e. not transfected) are radiosensitized by PTX, which alleviates the postirradiation G2/M-phase block