title: [18F]FLT PET for non-invasive assessment of tumor sensitivity to chemotherapy: studies with experimental chemotherapy TP202377 in human cancer xenografts in mice.
abstract: OBJECTIVE
  3'-deoxy-3'-[¹⁸F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use [18F]FLT positron emission tomography (PET) to study non-invasively early anti-proliferative effects of the experimental chemotherapeutic agent TP202377 in both sensitive and resistant tumors.
  
  
  METHODS
  Xenografts in mice from 3 human cancer cell lines were used: the TP202377 sensitive A2780 ovary cancer cell line (n = 8-16 tumors/group), the induced resistant A2780/Top216 cell line (n = 8-12 tumors/group) and the natural resistant SW620 colon cancer cell line (n = 10 tumors/group). In vivo uptake of [18F]FLT was studied at baseline and repeated 6 hours, Day 1, and Day 6 after TP202377 treatment (40 mg/kg i.v.) was initiated. Tracer uptake was quantified using small animal PET/CT.
  
  
  RESULTS
  TP202377 (40 mg/kg at 0 hours) caused growth inhibition at Day 6 in the sensitive A2780 tumor model compared to the control group (P<0.001). In the A2780 tumor model TP202377 treatment caused significant decrease in uptake of [18F]FLT at 6 hours (-46%; P<0.001) and Day 1 (-44%; P<0.001) after treatment start compared to baseline uptake. At Day 6 uptake was comparable to baseline. Treatment with TP202377 did not influence tumor growth or [18F]FLT uptake in the resistant A2780/Top216 and SW620 tumor models. In all control groups uptake of [18F]FLT did not change. Ki67 gene expression paralleled [18F]FLT uptake.
  
  
  CONCLUSIONS
  Treatment of A2780 xenografts in mice with TP202377 (single dose i.v.) caused a significant decrease in cell proliferation assessed by [18F]FLT PET after 6 hours. Inhibition persisted at Day 1; however, cell proliferation had returned to baseline at Day 6. In the resistant A2780/Top216 and SW620 tumor models uptake of [18F]FLT did not change after treatment. With [18F]FLT PET it was possible to distinguish non-invasively between sensitive and resistant tumors already 6 hours after treatment initiation.
authors.affiliation: Cluster for Molecular Imaging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. mettemj@sund.ku.dk
authors.forename: Mette
authors.initials: M
authors.lastname: Munk Jensen
authors.forename: Kamille Dumong
authors.initials: KD
authors.lastname: Erichsen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Björkling
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.forename: Peter Buhl
authors.initials: PB
authors.lastname: Jensen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Liselotte
authors.initials: L
authors.lastname: Højgaard
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000235:genetics; D051379:Mice; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D049268:Positron-Emission Tomography; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D007211:Indoles; D019394:Ki-67 Antigen; C581196:TP202377; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine