title: In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET.
abstract: BACKGROUND
  Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of (11)C 2'-fluoro-5-methyl-1-beta-d-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model.
  
  
  METHODS
  Adult beagles (n=8) with implanted brain tumors received [(11)C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m(2)) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomography-defined regions of interest were corrected for partial volume effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor volume occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[(11)C]FMAU and BUdR were compared by linear regression analysis and analysis of variance, as well as by a nonparametric rank correlation test.
  
  
  RESULTS
  Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6+/-0.4 and 5.5+/-1.2 (n=8; mean+/-S.E.M.), respectively. No (11)C-labeled metabolites were observed in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k(4)=0) and by Patlak analysis. Parametric statistical analysis showed that FMAU clearance from plasma into tumor Compartment 3 (K(FMAU)) was significantly correlated with S-phase percent volume (P=.03), while tumor SUV was significantly correlated with both S-phase percent volume and cell percent volume (P=.02 and .03, respectively). Patlak slope, K(FMAU) and tumor SUV were equivalent with regard to rank correlation analysis, which showed that tumor uptake and trapping of FMAU were correlated with the volume density of dividing cells (P=.0003) rather than nondividing cells (P=.3).
  
  
  CONCLUSIONS
  Trapping of [(11)C]FMAU correlated with tumor growth rate, as measured by direct tissue analysis with BUdR in a canine brain tumor model, suggesting that [(11)C]FMAU is useful for the imaging of cell proliferation in cancers.
authors.affiliation: PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA. pconti@usc.edu
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
authors.forename: James R
authors.initials: JR
authors.lastname: Bading
authors.forename: Peter P
authors.initials: PP
authors.lastname: Mouton
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Links
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: John D
authors.initials: JD
authors.lastname: Fissekis
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: James H
authors.initials: JH
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D002250:Carbon Radioisotopes; D049109:Cell Proliferation; D004285:Dogs; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D001086:Arabinofuranosyluracil; C034935:clevudine