ABSTRACT
Purpose. In this study, we evaluated our experience with salvage brachytherapy after discovery of biochemical recurrence after a prior brachytherapy procedure. Methods and Materials. From 2001 through 2012 twenty-one patients treated by brachytherapy within University of Kentucky or from outside centers developed biochemical failure and had no evidence of metastases. Computed tomography (CT) scans were evaluated; patients who had an underseeded portion of their prostate were considered for reimplantation. Results. The majority of the patients in this study (61.9%) were low risk and median presalvage PSA was 3.49 (range 17.41-1.68). Mean follow-up was 61 months. At last follow-up after reseeding, 11/21 (52.4%) were free of biochemical recurrence. There was a trend towards decreased freedom from biochemical recurrence in low risk patients (p = 0.12). International Prostate Symptom Scores (IPSS) increased at 3-month follow-up visits but decreased and were equivalent to baseline scores at 18 months. Conclusions. Salvage brachytherapy after primary brachytherapy is possible; however, in our experience the side-effect profile after the second brachytherapy procedure was higher than after the first brachytherapy procedure. In this cohort of patients we demonstrate that approximately 50% oncologic control, low risk patients appear to have better outcomes than others.
ABSTRACT
Elevated oxidative stress is observed more frequently in cancer cells than in normal cells. It is therefore expected that additional exposure to a low level of reactive oxygen species (ROS) will push cancer cells toward death, whereas normal cells might maintain redox homeostasis through adaptive antioxidant responses. We previously showed that parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase. The present study identifies KEAP1 as the downstream redox target that contributes to parthenolide's radiosensitization effect in prostate cancer cells. In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury. Mechanistically, parthenolide increases the level of cellular ROS and causes oxidation of thioredoxin (TrX) in prostate cancer cells, leading to a TrX-dependent increase in a reduced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and Bcl-xL (BCL2L1) degradation. In contrast, parthenolide increases oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 (NFE2L2) levels and subsequent Nrf2-dependent expression of antioxidant enzymes. These results reveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of parthenolide on tumor and normal cell radiosensitivity. Furthermore, they show it is possible to develop a tumor-specific radiosensitizing agent with radioprotective properties in normal cells.
