Mechanisms of radiosensitization by anti-cancer agents in prostate cancer models

Prostate cancer is often treated with radiotherapy, which is limited by damage to surrounding normal tissue. One way to address this limitation is to use a radiosensitizing agent that enhances tumor cell killing to a greater extent than normal tissue (i.e., differential radiosensitization). Thus, the goals of my research are 1) to identify compounds which can radiosensitize prostate tumors without causing adverse effects upon normal tissue; and 2) to elucidate the molecular mechanisms of synergism. Our leading candidate is 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite with anti-tumor and anti-angiogenic properties. Recent Phase II clinical trials have shown that 2ME2 has limited anti-cancer efficacy as a single agent and is well-tolerated in patients. We have previously demonstrated that 2ME2 is a radiosensitizer against lung cancer cells (Amorino et. al., Radiation Research, 2000, 153: 384-91) and recently in prostate cancer models in vitro and in vivo (Casarez et. al., Cancer Research, 2007 - in press). Furthermore, we have implicated the Mitogen-Activated Protein Kinase (MAPK) in the mechanism of synergism. Our second agent of interest is SR48692, a specific inhibitor of the neurotensin receptor (NTR1). We have shown that SR48692 can radiosensitize prostate cancer cells that express NTR1, but not normal prostate cells (NTR-1 negative). Current studies are focused upon in vivo work with SR48692 + radiation, as well as continued mechanistic studies with 2ME2 + radiation.