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-Radiation-induced G₂ Delay, Apoptosis, and p53 Response as Potential Susceptibility Markers For Lung Cancer

Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [H. Zhao, M. R. S., H. Zhan., X. W.]; The University of Texas—School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas 77030 [H. Zhao]; and The University of Texas Southwestern Medical Center, Hamon Cancer for Therapeutic Oncology Research, Dallas, Texas 75390 [G. E. T., J. D. M.]

-Radiation results in cell cycle arrest and apoptosis in a wide variety of cells. Cell cycle arrest provides time for the cell to repair damaged DNA before entering the next phase of the cycle. If the damage is severe and cannot be repaired, the cells undergo apoptosis. However, if the damaged cells continue to grow without repair or apoptosis, then carcinogenic transformation may occur. We hypothesized that individuals with inherited disruption in cell cycle control and/or apoptosis and/or DNA repair may be susceptible to lung cancer development. The cells from susceptible individuals would have a shorter G₂ period and less apoptosis compared with cells from normal individuals upon exposure to -radiation. To test this hypothesis, the following methods were used: (a) fluorescence-activated cell sorting method was used to measure apoptosis and G₂ cell cycle delay; (b) the ELISA method was used to measure p53 protein expression levels in these cell lines; and (c) -radiation-induced chromatid breaks were counted as a marker for DNA damage or repair. Next, -radiation-induced G₂ delay and apoptosis were tested in three lymphoblastoid cell lines to determine the dose response effect and optimal time points of -radiation. Finally, these assays were tested in lymphoblastoid cell lines from 30 lung cancer patients and 22 healthy controls. We found a dose-response relationship for -radiation-induced G₂ delay and apoptosis. The optimal time points to detect differential G₂ delay and apoptotic index were 10 h and 48 h after -radiation, respectively. The mean G₂ delay was 22.5% ± 10.5% for the control cell lines and 14.71% ± 8.8% for case cell lines (P < 0.01). The mean apoptotic index was 20.4% ± 11.7% for the controls and 14.3% ± 7.8% for the cases (P < 0.05). The controls had a significantly higher p53 response ratio and fewer chromatid breaks than the cases. We also found that a p53 increasing ratio was strongly related to cell cycle G₂ delay ( = 0.413; P = 0.002) and chromatid breaks ( =0.384; P = 0.028). Therefore, we concluded that -radiation-induced G₂ delay, apoptosis, p53 increasing ratio, and chromatid breaks might potentially be used as susceptibility markers for lung cancer risk. A large epidemiology study is in progress to confirm these findings.

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