title: Tumor 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) uptake by PET correlates with thymidine kinase 1 expression: static and kinetic analysis of (18)F-FLT PET studies in lung tumors.
abstract: We report the first, to our knowledge, findings describing the relationships between both static and dynamic analysis parameters of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and the expression of the proliferation marker Ki-67, and the protein expression and enzymatic activity of thymidine kinase-1 (TK1) in surgically resected lung lesions.
  
  
  METHODS
  Static and dynamic analyses (4 rate constants and 2 compartments) of (18)F-FLT PET images were performed in a cohort of 25 prospectively accrued, clinically suspected lung cancer patients before surgical resection (1 lesion was found to be benign after surgery). The maximal and overall averaged expression of Ki-67 and TK1 were determined by semiquantitative analysis of immunohistochemical staining. TK1 enzymatic activity was determined by in vitro assay of extracts prepared from flash-frozen samples of the same tumors.
  
  
  RESULTS
  Static (18)F-FLT uptake (partial-volume-corrected maximum-pixel standardized uptake value from 60- to 90-min summed dynamic data) was significantly correlated with the overall (ρ = 0.57, P = 0.006) and maximal (ρ = 0.69, P < 0.001) immunohistochemical expressions of Ki-67 and TK1 (overall expression: ρ = 0.65, P = 0.001; maximal expression: ρ = 0.68, P < 0.001) but not with TK1 enzymatic activity (ρ = 0.34, P = 0.146). TK1 activity was significantly correlated with TK1 protein expression only when immunohistochemistry was scored for maximal expression (ρ = 0.52, P = 0.029). Dynamic analysis of (18)F-FLT PET revealed correlations between the flux constant (K(FLT)) and both overall (ρ = 0.53, P = 0.014) and maximal (ρ = 0.50, P = 0.020) TK1 protein expression. K(FLT) was also associated with both overall (ρ = 0.59, P = 0.005) and maximal (ρ = 0.63, P = 0.002) Ki-67 expression. We observed no significant correlations between TK1 enzyme activity and K(FLT). In addition, no significant relationships were found between TK1 expression, TK1 activity, or Ki-67 expression and any of the compartmental rate constants.
  
  
  CONCLUSIONS
  The absence of observable correlations of the imaging parameters with TK1 activity suggests that (18)F-FLT uptake and retention within cells may be complicated by a variety of still undetermined factors in addition to TK1 enzymatic activity.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Washington School of Medicine, Seattle, WA 98195-7115, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Brockenbrough
authors.forename: Timothee
authors.initials: T
authors.lastname: Souquet
authors.forename: Janice K
authors.initials: JK
authors.lastname: Morihara
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Stern
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Hawes
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rasey
authors.forename: Antoine
authors.initials: A
authors.lastname: Leblond
authors.forename: Linda W
authors.initials: LW
authors.lastname: Wiens
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Feng
authors.forename: John
authors.initials: J
authors.lastname: Grierson
authors.forename: Hubert
authors.initials: H
authors.lastname: Vesselle
mesh_terms: D002453:Cell Cycle; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007700:Kinetics; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011379:Prognosis; D013937:Thymidine Kinase / Q000096:biosynthesis*; D013997:Time Factors
chemical_list: D019394:Ki-67 Antigen; D019788:Fluorodeoxyglucose F18; D013937:Thymidine Kinase; C092717:thymidine kinase 1