title: Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor.
abstract: OBJECTIVE
  Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor.
  
  
  METHODS
  The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward.
  
  
  RESULTS
  On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens.
  
  
  CONCLUSIONS
  Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.
authors.affiliation: Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908, USA. jps2f@virginia.edu
authors.forename: Jason P
authors.initials: JP
authors.lastname: Sheehan
authors.forename: Britney
authors.initials: B
authors.lastname: Popp
authors.forename: Stephen
authors.initials: S
authors.lastname: Monteith
authors.forename: Sushila
authors.initials: S
authors.lastname: Toulmin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tomlinson
authors.forename: Jessica
authors.initials: J
authors.lastname: Martin
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cifarelli
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Deric M
authors.initials: DM
authors.lastname: Park
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D002338:Carotenoids; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000473:pathology*; D005909:Glioblastoma / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D000860:Hypoxia / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D009368:Neoplasm Transplantation; D011877:Radionuclide Imaging; D051381:Rats; D014801:Vitamin A / Q000031:analogs & derivatives*
chemical_list: C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids