[en] Purpose: Approximately 30% of human glial tumors exhibit mutant forms of p53 and 80% express abnormal levels of p53 protein as seen using immunohistochemical techniques. Therefore a majority of glioblastomas may suffer a functional loss of p53 activity either by a mutant p53 gene or by a functional neutralization of normal p53 activities. The p53 gene product plays an important role in mediating radiation induced G1-S cell cycle arrest and apoptosis in normal cells. We attempt to determine if rat glioblastoma tumors exhibit increased radiosensitivity when transfected with wild type p53 and treated with high dose, single fraction irradiation. Materials and Methods: Cultures of RT2 glioblastoma cells were infected with nonreplicative adenoviral vectors containing either the wild-type p53 gene (AdVp53) or the LacZ gene (AdVLacZ). Tumors were grown intracranially in Fisher female rats. Treatment groups included; a) AdVp53, b) AdVlacZ, c) non-tranfected tumor cells. Half of each group received precision 6MV linac delivered irradiation using an adapted 13mm extended collimator and specialized immobilization. The tumors were treated to a dose of 15 Gy given in a single fraction (dose rate = 2.4 Gy/minute). Some animals in each assigned treatment group were sacrificed 24 and 48 hours after irradiation and tumors were sampled and subjected to the TUNEL assay to determine the extent of apoptosis. The remaining animals were observed until death. Results: Cultures infected with AdVp53 effectively expressed increased amounts of wild-type p53 protein as determined by western blot analysis. Median rat survival times were 12 days in control animals receiving no radiation, 14 days in control rats given irradiation and 18 days in AdVp53 transfected animals treated with irradiation. Increased apoptosis was demonstrated at 24 and 48 hours in AdVp53 rats as compared to controls receiving radiation only (50% vs. 15%). Conclusion: We have demonstrated in vivo radiosensitization/increased apoptosis of rat glioblastoma(AdVp53) tumors treated with large fraction irradiation. A comparison to other radiation modifiers (tirapazamine, RSR-13, IUDR) in this tumor system will also be discussed

[en] It has been suggested that continued tobacco use during radiation therapy contributes to maintenance of neoplastic growth despite treatment with radiation. Nicotine is a cigarette component that is an established risk factor for many diseases, neoplastic and otherwise. The hypothesis of this work is that nicotine promotes the proliferation, migration, and radioresistance of human malignant glioma cells. The effect of nicotine on cellular proliferation, migration, signaling, and radiation sensitivity were evaluated for malignant glioma U87 and GBM12 cells by use of the AlamarBlue, scratch healing, and clonogenic survival assays. Signal transduction was assessed by immunoblotting for activated EGFR, extracellular regulated kinase (ERK), and AKT. At concentrations comparable with those found in chronic smokers, nicotine induced malignant glioma cell migration, growth, colony formation, and radioresistance. Nicotine increased phosphorylation of EGFR^tyr992, AKT^ser473, and ERK. These molecular effects were reduced by pharmacological inhibitors of EGFR, PI3K, and MEK. It was therefore concluded that nicotine stimulates the malignant behavior of glioma cells in vitro by activation of the EGFR and downstream AKT and ERK pathways. (author)