title: In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2'-deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models.
abstract: Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug.
  
  
  
  [18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized.
  
  
  
  In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. russellj@mskcc.org.
authors.forename: James
authors.identifier: 0000-0003-0827-1801
authors.initials: J
authors.lastname: Russell
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.affiliation: Research Animal Resource Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Kramer
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Romesser
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Desai
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Lowery
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003596:Cytosine / Q000494:pharmacology / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008819:Mice, Nude; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D003596:Cytosine; D000093542:Gemcitabine
keywords: FAC; Gemcitabine; Pancreatic cancer