NIH 3T3 fibroblast cells, transformed with activated forms of Ras, only supported reovirus replica tion if signalling Tubacin side effects from Ras to RalGEFp38MAPK was in tact. When p38MAPK was inhibited in melanoma, reovirus induced oncolysis was abrogated. Inhibitors,Modulators,Libraries Together, this indicates that activity in the p38MAPK pathway is a determinant of sensitivity to reovirus in these cell types. Alternatively, in C26 colorectal tumour cells, reovirus induced cell death was found to be distinct from Ras sta tus and viral replication. In either the presence or ab sence of mutant Ras, C26 cells supported reovirus replication but expression of mutated Ras increased the sensitivity of tumour cells to reovirus induced apoptosis. Additional influences of Ras pathway status on the effects of reovirus infection have been highlighted by Marcato et al.

who demonstrated significantly enhanced proteolytic disassembly of reovirus in Ras transformed NIH 3T3 cells. They also showed Inhibitors,Modulators,Libraries that Ras transformation increases the infectious non infectious particle ratio and promotes caspase mediated release and spread of viral progeny. In spite of differences in the reported mechanism of killing, preclinical studies in a wide range of in vitro and in vivo models, including intratumoural and intravenous injections in immune deficient and competent mice, have clearly shown that reovirus has a broad spectrum of oncolytic activity. Clinical testing of reovirus through a strong translational programme is well advanced following phase I and II studies as a single agent and in combination with cytotoxic chemo therapy or radiotherapy.

Consequently, reovirus is currently being tested under a Special Proto col Agreement from the US Federal Drug Administra tion in a randomised phase III study of carboplatin and paclitaxel plus either placebo or reovirus Inhibitors,Modulators,Libraries in patients with relapsedmetastatic SCCHN. Overexpression of epidermal growth factor receptor and consequent Inhibitors,Modulators,Libraries activation of the Inhibitors,Modulators,Libraries Ras signalling pathway is the dominant oncogenic process in SCCHN. Specific anti EGFR monoclonal antibodies have already shown clinical benefits in newly diagnosed and relapsedmetastatic SCCHN and it is likely that novel agents that target the EGFRRas axis will be active in this disease. Therefore, we have conducted a detailed analysis of the effects of reovirus in a panel of head and neck cancer cell lines.

Both pre and post entry events have been studied in an attempt to define biomarkers that will predict for sensitivityresistance to reoviral ther apy. In particular, cause we have analysed the role of the EGFRRas signalling pathway in determining virus mediated cytotoxicity in SCCHN. Results Reovirus is active against a panel of head and neck cancer cell lines We initially sought to profile and define the sensitivity of human head and neck tumour cells to reovirus induced oncolysis.