Enhancing the Effect of Radiation Therapy Using Non-Steroidal Anti-Inflammatory Agents
Final rept. 1 Oct 1998-31 Aug 2002
NATIONAL INSTITUTES OF HEALTH BETHESDA MD
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Our earlier studies demonstrated that ibuprofen sensitizes prostate cancer cells to radiation in vitro and in vivo. The cytotoxic and radiosensitizing effects of NSAIDs were seen at concentrations that are higher than those that inhibit prostaglandin synthesis. To understand the molecular mechanisms involved in radiosensitization we examined the effects of ibuprofen on several potential cellular targets including COX-2 and transcription factors NFkB and HIFs. NFkB regulates cytokines, growth factors and controls apoptotic pathways. Ibuprofen inhibited constitutive as well as cytokine- or radiation-induced NFkB. Tumor cells in hypoxic environment are resistant to cancer therapies including radiation, although the role of HIFs in this effect is not clear. HIFs are key regulators of tumor growth and angiogenesis, and are over expressed in the majority of common human tumors. Since NSAIDs inhibit angiogenesis we determined the effect of the NSAlDs on HIFs. Ibuprofen treatment rapidly reduced HIF proteins with a subsequent reduction in the HIF-regulated gene products VEGF and Glut- 1 under hypoxia in vitro. We are currently evaluating the effects of radiation in combination with COX-2 specific inhibitors that appear to be relatively less toxic in clinic, on tumor growth and angiogenesis in vitro and in vivo. Preclinical studies using a combination of COX inhibitors is in progress in preparation for a clinical trial with molecular markers. The specific role of HIFs is being evaluated in HIF over expressing cells as another therapeutic target for radiosensitization. The results from this research project can be directly translated into the clinic with a potential to improve local tumor control, to reduce toxicity and increase overall survival.
- Medicine and Medical Research