• Kuno Lehmann, Andreas Rickenbacher, Jae-Hwi Jang, Christian E Oberkofler, René Vonlanthen, Lotta von Boehmer, Bostjan Humar, Rolf Graf, Philippe Gertsch, and Pierre-Alain Clavien.
• Laboratory of the Swiss Hepato-Pancreatico-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zurich, Ramistrasse 100, Zurich, Switzerland.
• Ann. Surg.. 2012 Nov 1;256(5):730-7; discussion 737-8.

BackgroundThe aim of hyperthermic intraperitoneal chemotherapy (HIPEC) is to eradicate microscopic residual tumor after radical surgical tumor excision in patients with peritoneal carcinomatosis. The common use of antineoplastic agents such as mitomycin C, doxorubicin, or oxaliplatin with hyperthermia fails to eradicate tumors in a significant subset of patients, and alternative approaches to target chemoresistant cells are needed. The induction of reactive oxygen species (ROS) by inhibiting the critical detoxification enzyme superoxide dismutase (SOD) during hyperthermia is an appealing approach to induce death of residual cancer cells.MethodsHuman and murine colon cancer cell lines were subjected to mild hyperthermia (40-42°C), and treated with chemotherapy, similar to clinical protocols. ROS were induced by the SOD inhibitor diethyldithiocarbamate (DDC), a metabolite of the drug disulfiram. In mice, peritoneal carcinomatosis use C57Bl/6 was induced in C57Bl/6 by intraperitoneal injection of syngenic tumor cells (MC38).ResultsHyperthermia alone failed to kill cells but induced intracellular ROS and activated protective mechanisms. Chemotherapy conferred inconsistent cytotoxicity depending on the cell line and dose. In contrast, induction of ROS by DDC consistently activated apoptotic pathways, with increased cell death in combination with mild hyperthermia. In vivo, combined treatment with DDC and hyperthermia significantly delayed tumor progression in tumor-bearing mice. In addition, hyperthermic combined treatment with chemotherapy and DDC significantly improved animal survival compared with chemotherapy alone.ConclusionsAddition of DDC improves the efficacy of existing HIPEC protocols in a safe way and may open the door to a more effective, multimodal HIPEC.

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