Enhancing radiation therapy for prostate cancer.

摘要

External beam radiation therapy (EBRT) is one of the few treatments for localized prostate cancer (CaP). Although it is initially effective, tumor recurrences are common. The cellular response to radiation-induced DNA damage includes cell cycle arrest, DNA repair, and cell death which combine to influence the survival of tumor cells following EBRT. Several studies have implicated the expression of the anti-apoptotic protein Bcl2 as an informative tumor marker for radiation response. Additionally, disruption of critical p53-regulated cell cycle checkpoints has been shown to accelerate entrance into M-phase and increase radiation-induced mitotic cell death. A greater understanding of radiation-response pathways may identify targets for enhancing this therapy. This dissertation, presented in three chapters, examines the biological response of prostate cancer cells to ionizing radiation.; Chapter I. We utilized genetically engineered prostate cancer cell lines to investigate the influence of Bcl2 on post-radiation cell survival. Over-expressing Bcl2 increased cell survival, and decreased cell survival was seen in the cells with down regulated Bcl2. These studies affirm the role of Bcl2 in CaP radiation resistance and support the concept of Bcl2 down-regulation as a potential strategy for enhancing radiosensitivity in prostate tumors.; Chapter II. Using three human prostate cancer cell lines, we examined cell cycle kinetics and cell survival following exposure to a clinically relevant radiation dose, in both single and multi-fraction investigations. These studies identified differences in radiation-induced cell cycle effects among the three cell lines that may predict responses to fractionated radiation therapy, and challenged the long-held assumption that equal-cell killing occurs with each dose administered.; Chapter III. We conditionally restored p53 function to p53-null prostate cancer cells to investigate its contributions to the radiation response. Functional p53 enhanced radiation-induced cell cycle arrest, and increased clonogenic survival following fractionated radiation. This suggests that wt p53 in tumor cells may reduce the effectiveness of EBRT by enhancing cell survival, and identifies certain p53 functions as attractive therapeutic targets.