title: [(18)F]FLT-PET imaging does not always "light up" proliferating tumor cells.
abstract: OBJECTIVE
  [(18)F]FLT (3'-Fluoro-3' deoxythymidine)-PET imaging was proposed as a tool for measuring in vivo tumor cell proliferation. The aim of this article was to validate the use of [(18)F]FLT-PET imaging for measuring xenograft proliferation and subsequent monitoring of targeted therapy.
  
  
  METHODS
  In exponentially growing xenografts, factors that could impact the outcome of [(18)F]FLT-PET imaging, such as nucleoside transporters, thymidine kinase 1, the relative contribution of DNA salvage pathway, and the ratio of FLT to thymidine, were evaluated. The [(18)F]FLT tracer avidity was compared with other proliferation markers.
  
  
  RESULTS
  In a panel of proliferating xenografts, [(18)F]FLT or [(3)H]thymidine tracer avidity failed to reflect the tumor growth rate across different tumor types, despite the high expressions of Ki67 and TK1. When FLT was injected at the same dose level as used in the preclinical [(18)F]FLT-PET imaging, the plasma exposure ratio of FLT to thymidine was approximately 1:200. Thymidine levels in different tumor types seemed to be variable and exhibited an inverse relationship with the FLT tracer avidity. In contrast, high-dose administration of bromdeoxyuridine (BrdUrd; 50 mg/kg) yielded a plasma exposure of more than 4-fold higher than thymidine and leads to a strong correlation between the BrdUrd uptake and the tumor proliferation rate. In FLT tracer-avid models, [(18)F]FLT-PET imaging as a surrogate biomarker predicted the therapeutic response of CDK4/6 inhibitor PD-0332991.
  
  
  CONCLUSIONS
  Tumor thymidine level is one of the factors that impact the correlation between [(18)F]FLT uptake and tumor cell proliferation. With careful validation, [(18)F]FLT-PET imaging can be used to monitor antiproliferative therapies in tracer-avid malignancies.
authors.affiliation: Oncology Research Unit, La Jolla Laboratories, Pfizer Global Research and Development, San Diego, California 92121, USA. cathy.zhang@pfizer.com
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Zhang
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Yan
authors.forename: Wenlin
authors.initials: W
authors.lastname: Li
authors.forename: Kyle
authors.initials: K
authors.lastname: Kuszpit
authors.forename: Cory L
authors.initials: CL
authors.lastname: Painter
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Lappin
authors.forename: Tim
authors.initials: T
authors.lastname: Nichols
authors.forename: Maruja E
authors.initials: ME
authors.lastname: Lira
authors.forename: Timothy
authors.initials: T
authors.lastname: Affolter
authors.forename: Neeta R
authors.initials: NR
authors.lastname: Fahey
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Mary
authors.initials: M
authors.lastname: Spilker
authors.forename: Kenneth
authors.initials: K
authors.lastname: Zasadny
authors.forename: Peter
authors.initials: P
authors.lastname: O'Brien
authors.forename: Dana
authors.initials: D
authors.lastname: Buckman
authors.forename: Anthony
authors.initials: A
authors.lastname: Wong
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D010879:Piperazines; D011725:Pyridines; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine; C500026:palbociclib; C002854:alovudine; D013936:Thymidine