title: Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study.
abstract: BACKGROUND
  The combined treatment modality of ionizing radiation (IR) with inhibitors of angiogenesis (IoA) is a promising treatment modality based on preclinical in vivo studies using heterotopic xeno- and allograft tumor models. Nevertheless reservations still exist to translate this combined treatment modality into clinical trials, and more advanced, spontaneous orthotopic tumor models are required for validation to study the efficacy and safety of this treatment modality.
  
  
  RESULTS
  We therefore investigated the combined treatment modality of IR in combination with the clinically relevant VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787 in the MMTV/c-neu induced mammary carcinoma model and a syngenic allograft tumor model using athymic nude mice. Mice were treated with fractionated IR, the VEGFR-inhibitor PTK787/ZK222584 (PTK787), or in combination, and efficacy and mechanistic-related endpoints were probed in both tumor models. Overall the treatment response to the IoA was comparable in both tumor models, demonstrating minimal tumor growth delay in response to PTK787 and PTK787-induced tumor hypoxia. Interestingly spontaneously growing tumors were more radiosensitive than the allograft tumors. More important combined treatment of irradiation with PTK787 resulted in a supraadditive tumor response in both tumor models with a comparable enhancement factor, namely 1.5 and 1.4 in the allograft and in the spontaneous tumor model, respectively.
  
  
  CONCLUSIONS
  These results demonstrate that IR in combination with VEGF-receptor tyrosine kinase inhibitors is a valid, promising treatment modality, and that the treatment responses in spontaneous mammary carcinomas and syngenic allografts tumor models are comparable.
authors.affiliation: Deptartment of Radiation Oncology, University Hospital Zurich, CH-8091 Zurich.
authors.forename: Oliver
authors.initials: O
authors.lastname: Riesterer
authors.forename: Christoph
authors.initials: C
authors.lastname: Oehler-Jänne
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Angela
authors.initials: A
authors.lastname: Broggini-Tenzer
authors.forename: Van
authors.initials: V
authors.lastname: Vuong
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011839:Radiation, Ionizing; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor