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ABSTRACTWild-type (wt) p53 DNA was transfected into the radioresistant human cell line JSQ-3, established from a squamous cell carcinoma of the head and neck (SCCHN), using a transferrinliposome system, and the ability of the introduced wt p53 to sensitize the transfected JSQ-3 cells to ionizing radiation was examined. Transferrin increased the in vitrotransfection efficiency of cationic liposomes up to 7080% in JSQ-3 cells, representing a 6- to 10-fold increase over liposome transfection alone. The exogenous wt p53 was expressed at high levels in transferrinliposomeDNA-transfected cells and resulted in the reversion of the radioresistant phenotype of the JSQ-3 cells in a DNA dose-dependent manner. The D10values were reduced from 6.36 0.54 Gy to 4.13 0.06 Gy, a value in the radiosensitive range. In vivo, the intratumoral injection of the transferrinliposome system resulted in a higher number of transfected tumor cells in the JSQ-3 induced nude mouse xenografts when compared with transfection by liposome alone. The results indicate that the combination of p53 replacement gene transduction, mediated by the relatively safe transferrinliposome system, and conventional ionizing radiation may provide a more effective treatment for head and neck cancer.