Adenovirus-mediated antisense ATM gene transfer sensitizes prostate cancercells to radiation

Treatment failure after radiation therapy of prostate cancer IPC) could be a significant problem. Our objective is to design genetic radiosensitizing strategies for the treatment of PC. Cells from individuals with the genetic disorder ataxia telangiectasia (AT) are hypersensitive to ionizing radiati on. Therefore, we examined whether attenuation of the AT gene product, AT m utated (ATM), in PC cells could result in an increased intrinsic radiosensi tivity. A p53-mutant PC cell line, PC-3 was infected with adenoviral vector s, expressing antisense ATM RNA to various domains of the ATM gene. Immunob lot analyses of cellular extracts from antisense A TM-transfected PC-3 cell s showed attenuated expression of the ATM protein within 2 days of viral in fection. Compared with cells infected with an adeno-beta -galactosidase vec tor, antisense ATM-transfected PC-3 cells showed aberrant control of S-phas e cell-cycle checkpoints after Exposure to ionizing radiation. Under these conditions, the intrinsic radiosensitivity of the PC-3 cells was enhanced. Consequently antisense ATM gene therapy could serve as a paradigm for strat egies that target the cellular survival mechanisms of an irradiated tumor c ell and may provide therapeutic benefit to patients undergoing radiation th erapy for PC.