title: Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate.
abstract: OBJECTIVE
  Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.
  
  
  METHODS
  We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.
  
  
  RESULTS
  ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.
  
  
  CONCLUSIONS
  Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. ©2016 AACR.
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Linecker
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kachaylo
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tschuor
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kron
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlegel
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Udo
authors.initials: U
authors.lastname: Ungethuem
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jae Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Research Unit, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Georgiopoulou
authors.affiliation: Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, Strasbourg, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland. clavien@access.uzh.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000494:pharmacology; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007295:Inositol Phosphates / Q000494:pharmacology*; D002955:Leucovorin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007295:Inositol Phosphates; D009944:Organoplatinum Compounds; D042461:Vascular Endothelial Growth Factor A; C516441:inositol trispyrophosphate; D002955:Leucovorin; D010100:Oxygen; D005472:Fluorouracil