title: Evaluation of 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas.
abstract: OBJECTIVE
  The thymidine analog 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of (18)F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood-brain barrier (BBB) breakdown in human brain gliomas.
  
  
  METHODS
  A total of 21 patients with newly diagnosed gliomas were examined by (18)F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of (18)F-FLT in the tumor and (18)F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.
  
  
  RESULTS
  (18)F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K (1); P = 0.001 and P < 0.001, respectively), but not with the phosphorylation rate constant (k (3)). IHC and real-time PCR studies demonstrated a significant correlation between K (1) and TK-1 mRNA expression (P = 0.001), but not between k (3) and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K (1) and the Ki-67 index (P = 0.003), but not between k (3) and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P = 0.009). (18)F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P = 0.003 and P = 0.011, respectively).
  
  
  CONCLUSIONS
  These results indicate that (18)F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k (3) determined by (18)F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.
authors.affiliation: Department of Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Shinomiya
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kawai
authors.forename: Masaki
authors.initials: M
authors.lastname: Okada
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kushida
authors.forename: Reiji
authors.initials: R
authors.lastname: Haba
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kudomi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tokuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Tamiya
mesh_terms: D000328:Adult; D000368:Aged; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D015224:Dideoxynucleosides / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016133:Polymerase Chain Reaction / Q000379:methods; D013937:Thymidine Kinase / Q000096:biosynthesis*
chemical_list: D015224:Dideoxynucleosides; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine