title: Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma.
abstract: BACKGROUND
  Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N'-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM.
  
  
  METHODS
  U251 human glioma cells (4×10(5)) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8-21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0-21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis.
  
  
  RESULTS
  Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0-21 days treatment), tumor volume, tumor blood volume, permeability, extravascular and extracellular space volume, tumor cell proliferation, and cell migration were decreased compared with that of the vehicle-treated group.
  
  
  CONCLUSIONS
  HET0016 is capable of controlling tumor growth and migration, but these effects are dependent on the timing of drug administration. The addition of HET0016 to vatalanib may attenuate the unwanted effect of vatalanib.
authors.affiliation: Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Laboratory of Molecular Investigation of Cancer (LIMC), Faculty of Medicine of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Brazil.
authors.forename: Thaiz F
authors.initials: TF
authors.lastname: Borin
authors.affiliation: Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Asm
authors.initials: A
authors.lastname: Iskander
authors.affiliation: Department of Radiology, Cellular and Molecular Imaging Laboratory, Detroit, MI, USA.
authors.forename: Nadimpalli Rs
authors.initials: NR
authors.lastname: Varma
authors.affiliation: Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Bhagelu R
authors.initials: BR
authors.lastname: Achyut
authors.affiliation: Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Meenu
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, USA.
authors.forename: Austin M
authors.initials: AM
authors.lastname: Guo
authors.affiliation: Department of Radiology, Cellular and Molecular Imaging Laboratory, Detroit, MI, USA.
authors.forename: Wilson B
authors.initials: WB
authors.lastname: Chwang
authors.affiliation: Department of Neurology and Radiology, Henry Ford Health System, Detroit, MI, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Ewing
authors.affiliation: Department of Neurology and Radiology, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bagher-Ebadian
authors.affiliation: Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
keywords: HET0016; antiangiogenic treatments; glioblastoma; magnetic resonance imaging; protein array; vascular parameters