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New Insight Into Hyperthermic Intraperitoneal Chemotherapy: Induction of Oxidative Stress Dramatically Enhanced Tumor Killing in In Vitro and In Vivo Models

Lehmann, Kuno MD*; Rickenbacher, Andreas MD*; Jang, Jae-Hwi PhD*; Oberkofler, Christian E. MD*; Vonlanthen, René MD*; von Boehmer, Lotta MD; Humar, Bostjan PhD*; Graf, Rolf MD*; Gertsch, Philippe MD*; Clavien, Pierre-Alain MD, PhD*

doi: 10.1097/SLA.0b013e3182737517
Original Articles From the ESA Proceedings

Background: The 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.

Methods: Human 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).

Results: Hyperthermia 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.

Conclusions: Addition of DDC improves the efficacy of existing HIPEC protocols in a safe way and may open the door to a more effective, multimodal HIPEC.

Induction of reactive oxygen species by inhibiting the enzyme superoxide dismutase during hyperthermia with diethyldithiocarbamate increased cell death in combination with mild hyperthermia. In a murine peritoneal carcinomatosis model, hyperthermic intraperitoneal chemotherapy with diethyldithiocarbamate and hyperthermia significantly delayed tumor progression in tumor-bearing mice and improved survival in combination with chemotherapy.

*Laboratory of the Swiss Hepato-Pancreatico-Biliary (HPB) and Transplantation Center, Department of Surgery

Department of Oncology, University Hospital Zurich, Zurich, Switzerland.

Reprints: Pierre-Alain Clavien, MD, PhD, Department of Surgery, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland. E-mail: clavien@access.uzh.ch.

This work was supported by a grant from the “Kurt und Senta Hermann” foundation to K.L., and the Liver and Gastrointestinal Disease (LGID) Foundation to PAC.

Disclosure: The authors declare no conflicts of interest.

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Abbreviations: CRC, colorectal cancer; DDC: diethyldithiocarbamate; HIPEC, hyperthermic intraperitoneal chemotherapy; ROS: reactive oxygen species; SOD: superoxide dismutase.

© 2012 Lippincott Williams & Wilkins, Inc.