51. New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models
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René Vonlanthen, Bostjan Humar, Rolf Graf, Kuno Lehmann, Andreas Rickenbacher, Philippe Gertsch, Pierre-Alain Clavien, Christian E. Oberkofler, Jae-Hwi Jang, Lotta von Boehmer, University of Zurich, and Lehmann, Kuno
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Hyperthermia ,medicine.medical_specialty ,medicine.medical_treatment ,Mitomycin ,Intraperitoneal injection ,Blotting, Western ,610 Medicine & health ,Antineoplastic Agents ,In Vitro Techniques ,Mice ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Doxorubicin ,Peritoneal Cavity ,10217 Clinic for Visceral and Transplantation Surgery ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Hydrogen Peroxide ,Hyperthermia, Induced ,Neoplasms, Experimental ,medicine.disease ,Combined Modality Therapy ,2746 Surgery ,Oxaliplatin ,Surgery ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Tumor progression ,Chemotherapy, Cancer, Regional Perfusion ,Colonic Neoplasms ,Cancer research ,Hyperthermic intraperitoneal chemotherapy ,business ,Ditiocarb ,Reactive Oxygen Species ,medicine.drug - Abstract
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.