DELAYED MOLECULAR RESPONSES TO BRAIN IRRADIATION

The chance of life-threatening complications occurring late after brai n irradiation limits the efficacy of this form of cancer therapy. The molecular and cellular events that trigger radiation-induced brain dam age are still unknown, but since they have the potential to serve as v aluable targets for therapeutic intervention they are worth delineatin g. In this murine study, the effect of irradiation on the expression o f molecules which are known to contribute to brain damage in other mod el systems was examined. Expression of genes encoding cytokines (TNF-a lpha/beta, IL-1 alpha/beta, IL-2, IL-3, IL-4, IL-5, IL-6 and IFN-gamma ), cytokine receptors (TNF-Rp55 and p75, IL-1R- p60 and p80, IFN-gamma R, and IL-6R), the cell adhesion molecule (ICAM-1), inducible nitric oxide synthetase (iNOS), anti-chymotrypsin (EB22/5.3), and the gliotic marker (GFAP) was evaluated over a 6-month period using a sensitive R Nase protection assay (RPA). We had previously demonstrated that withi n 24 h of brain irradiation there is an acute transitory molecular res ponse involving TNF-alpha, IL-1, ICAM-1, EB22/5.3 and GFAP. This study shows re-elevation of TNF-alpha, EB22/5.3 and GFAP mRNA levels at 2-3 months, but only TNF-alpha mRNA was overexpressed at 6 months. These time points are when neurological abnormalities are seen after higher doses. The data suggest that TNF-alpha may be involved in late brain r esponses to irradiation and could contribute to clinical symptoms.