title: Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET.
abstract: The aim of this study was to evaluate, whether PET with (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) may be used to monitor noninvasively the antiproliferative effects of tyrosine kinase inhibitors.
  
  
  METHODS
  Using a high-resolution small animal scanner, we measured the effect of the ErbB-selective kinase inhibitor PKI-166 on the (18)F-FDG and (18)F-FLT uptake of ErbB1-overexpressing A431 xenograft tumors.
  
  
  RESULTS
  Treatment with PKI-166 markedly lowered tumor (18)F-FLT uptake within 48 h of drug exposure; within 1 wk (18)F-FLT uptake decreased by 79%. (18)F-FLT uptake by the xenografts significantly correlated with the tumor proliferation index as determined by proliferating cell nuclear antigen staining (r = 0.71). Changes in (18)F-FLT uptake did not reflect inhibition of ErbB kinase activity itself but, rather, the effects of kinase inhibition on tumor cell proliferation. Tumor (18)F-FDG uptake generally paralleled the changes seen for (18)F-FLT. However, the baseline signal was significantly lower than that for (18)F-FLT.
  
  
  CONCLUSIONS
  These results indicate that (18)F-FLT PET provides noninvasive, quantitative, and repeatable measurements of tumor cell proliferation during treatment with ErbB kinase inhibitors and provide a rationale for the use this technology in clinical trials of kinase inhibitors.
authors.affiliation: Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Waldherr
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Halpern
authors.forename: Nora
authors.initials: N
authors.lastname: Rozengurt
authors.forename: Arash
authors.initials: A
authors.lastname: Safaei
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.forename: David
authors.initials: D
authors.lastname: Stout
authors.forename: Nagichettiar
authors.initials: N
authors.lastname: Satyamurthy
authors.forename: Jorge
authors.initials: J
authors.lastname: Barrio
authors.forename: Michael E
authors.initials: ME
authors.lastname: Phelps
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Silverman
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Johannes
authors.initials: J
authors.lastname: Czernin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000000981:diagnostic imaging* / Q000517:prevention & control*; D049268:Positron-Emission Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C410026:PKI 166; C002854:alovudine