Modulation of Apoptosis-Associated and DNA Repair Genes to Enhance Radiation Therapy

摘要

Of the approximately 220,900 men in the United States diagnosed with carcinoma of the prostate (CaP) in 2003, approximately eighty-five percent presented with presumed localized disease for which external beam radiation therapy (EBRT) was one of the few treatment options. While it is relatively effective, the failure rate still remains unacceptably high with a 5-year biochemical failure rate of 10-40%. The curative potential of radiation therapy still remains to be maximized. Genes that may be critical in controlling radiosensitivity are several that function in the G2 cell cycle phase arrest checkpoint after cellular radiation damage, and DNA damage repair mechanisms. p53 is a tumor suppressor gene that has a crucial role in the molecular pathway following genotoxic insult. It encodes a DNA-binding protein that transactivates genes that either influence survival through cell cycle arrest and DNA damage repair, or signal apoptosis in extensively damaged cells. Using a model system in which p53 function was conditionally restored to a p53-null PC3 prostate cancer cells by stable transfection with a human CaP-derived temperature-sensitive p53 tsp530 mutant allele, we have shown that functional p53 significantly increased clonogenic survival.