title: New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models.
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.
authors.affiliation: Laboratory of the Swiss Hepato-Pancreatico-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zurich, Ramistrasse 100, Zurich, Switzerland.
authors.forename: Kuno
authors.initials: K
authors.lastname: Lehmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Rickenbacher
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Christian E
authors.initials: CE
authors.lastname: Oberkofler
authors.forename: René
authors.initials: R
authors.lastname: Vonlanthen
authors.forename: Lotta
authors.initials: L
authors.lastname: von Boehmer
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Philippe
authors.initials: P
authors.lastname: Gertsch
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004050:Ditiocarb; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006979:Hyperthermia, Induced; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000008:administration & dosage* / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy; D018384:Oxidative Stress; D010529:Peritoneal Cavity; D017382:Reactive Oxygen Species / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D016685:Mitomycin; D004050:Ditiocarb; D006861:Hydrogen Peroxide