pd-0325901 and Fibrosarcoma

The relevance of Mitogen Activated Protein Kinase (MAPK) inhibitors as co-treatments for radiation therapy is investigated, with special focus on a potential link between the MAPK pathway and tumor hypoxia, which is a critical determinant for response to therapy.. The effects of two MAPK inhibitors, Sorafenib and PD0325901, were monitored daily using in vivo EPR (Electron Paramagnetic Resonance) oximetry in FSaII and TLT tumor models in order to identify a window of reoxygenation, during which tumor blood flow, oxygen consumption and radiation sensitivity were assessed.. Reoxygenation was shown after two days of treatments with Sorafenib or PD0325901 in two tumor models, which was further successfully exploited with Sorafenib for improving the radiation response of FSaII tumors by a factor of 1.5. The increase in tumor oxygenation was shown to be the result of two major factors: (i) an increase in blood flow for Sorafenib, that might be linked to its anti-angiogenic effect (vascular normalization), and (ii) a decrease in oxygen consumption for Sorafenib and PD0325901, due to an alteration of the mitochondrial activity.. We evidenced tumor reoxygenation in vivo following MAPK inhibition and suggest a rationale for the combination of radiation therapy with Sorafenib.

Topics: Angiogenesis Inducing Agents; Animals; Apoptosis; Benzamides; Blotting, Western; Diphenylamine; Electron Spin Resonance Spectroscopy; Fibrosarcoma; Glutathione; Liver Neoplasms, Experimental; Mice; Neoplasms, Experimental; Niacinamide; Oxygen Consumption; Phenylurea Compounds; Protein Kinase Inhibitors; Radiation Tolerance; Sorafenib