Efficacy of vorinostat-sensitized intraperitoneal radioimmunotherapy with Cu-64-labeled cetuximab against peritoneal dissemination of gastric cancer in a mouse model

Background: Gastric cancer is a common cause of cancer-related death worldwide, and peritoneal dissemination is the most frequent metastatic pattern of gastric cancer. However, the treatment of this disease condition remains difficult. It has been demonstrated that intraperitoneal radioimmunotherapy (ipRIT) with Cu-64-labeled cetuximab (anti-epidermal growth factor receptor antibody; Cu-64-cetuximab) is a potential treatment for peritoneal dissemination of gastrointestinal cancer in vivo. Recent preclinical and clinical studies have also shown that a histone deacetylase inhibitor, vorinostat, effectively sensitized gastrointestinal cancer to external radiation. Aim: In the present study, we examined the efficacy of the combined use of vorinostat, as a radiosensitizer during ipRIT with Cu-64-cetuximab in a peritoneal dissemination mouse model with human gastric cancer NUGC4 cells stably expressing red fluorescent protein. Methods: The mouse model was treated by ipRIT with Cu-64-cetuximab plus vorinostat, each single treatment, or saline (control). Side effects, including hematological and biochemical parameters, were evaluated in similarly treated, tumor-free mice. Results: Coadministration of ipRIT with Cu-64-cetuximab + vorinostat significantly prolonged survival compared to control and each single treatment. No significant toxicity signals were observed in all treatment groups. Conclusions: Our data suggest that vorinostat is a potentially effective radiosensitizer for use during the treatment of peritoneal dissemination of gastric cancer by ipRIT with Cu-64-cetuximab.