Interferon Gamma Induces Cell Cycle Arrest and Apoptosis in a Model of Ovarian Cancer: Enhancement of Effect by Batimastat

Locoregional human IFN-gamma may have activity against refractory ovarian cancer. We investigated this further in an ovarian cancer xenograft model. Administered at clinically relevant doses, intraperitoneal IFN-gamma prolonged the survival of mice bearing multiple established peritoneal tumours, with optimal treatment giving a 3-6-fold increase in median survival time. Daily dosing, which was superior to intermittent treatment, decreased DNA synthesis and induced apoptosis in tumour cells with maximal effects after 7-21 days treatment. This was preceded by an increase in p53 protein at 48 h. The effect of IFN-gamma was not enhanced by sequential treatment with carboplatin. However, the matrix metalloprotease inhibitor, batimastat, further increased mouse survival when given after IFN-gamma. Thus IFN-gamma is cytotoxic to ovarian epithelial cells in vivo and intensive locoregional dosing over short periods is effective. Sequential administration of novel agents that perturb the host/tumour relationship may be of benefit.