In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET.
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.
Conti
Peter S
PS
PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA. pconti@usc.edu
Bading
James R
JR
Mouton
Peter P
PP
Links
Jonathan M
JM
Alauddin
Mian M
MM
Fissekis
John D
JD
Ravert
Hayden T
HT
Hilton
John
J
Wong
Dean F
DF
Anderson
James H
JH
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
D002250:Carbon Radioisotopes; D001086:Arabinofuranosyluracil; C034935:clevudine