Preclinical Investigations of a Novel Small Molecule Radiosensitizer of Prostate Cancer.

摘要

The radiation therapy (RT) has proven to be effective at increasing survival of men with prostate cancer. However, the results are far from optimal, with 30- 40% of men with intermediate to high risk prostate cancer failing within 5 years. We have been investigating agents that have the potential to enhance the cell killing effects of one or both of these treatments. NS-123 is a drug that we have identified as having such potential. The objective of any combination of therapeutic agents is to achieve an improved therapeutic gain. The therapeutic gain is a function of both the tumor and normal tissue response. There is no universally accepted measure of a therapeutic result: lifespan, duration of remission, quality of life are all important and reflect different facets of the total result. When therapies are compared, it is necessary to show that one treatment controls the disease better than another for a similar level of toxicity. We recently reported the results of preclinical studies on a novel radiosensitizer, 4'-bromo-3'-nitropropiophenone (NS-123) that we identified using a cell-based, high-throughput screening method. In these studies, NS-123 radiosensitized human lung adenocarcinoma, colon adenocarcinoma, and glioma cells. Recently, we have demonstrated that NS- 123 also radiosensitizes prostate cancer cells. Importantly, NS-123 appears to be a true radiosensitizer as no overt toxicity was seen in any of the normal tissue models that we studied. Investigations into the mechanisms responsible for this radiosensitization suggest that NS-123 inhibits the DNA repair pathways, possible as a result of some upstream inhibition within the phosphatidylinositol-3-kinase/Akt pathway. NS-123 appears to sensitize prostate cancer cells with only a short exposure of 1 hr. Animal studies withdaily treatment (50 mg/kg) showed no toxicity. Studies investigating in vivo radiosensitization have been initiated.