title: The Thymidine Phosphorylase Imaging Agent 123I-IIMU Predicts the Efficacy of Capecitabine.
abstract: Recently, companion diagnostics with nuclear medicine techniques have been anticipated as more suitable means than biopsy for predicting treatment efficacy. The anticancer effect of capecitabine, an orally administered chemotherapeutic agent activated by thymidine phosphorylase (TP), is positively associated with tumor TP expression levels. This study aimed to assess whether TP imaging using a radiolabeled uracil derivative, (123)I-5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ((123)I-IIMU), could predict the efficacy of capecitabine treatment.
  
  
  
  Sensitivity to doxifluridine, a metabolite of capecitabine and direct substrate for TP, was assessed by water-soluble tetrazolium salt assays in vitro for 3 human colon cancer cell lines with different TP expression profiles. The intracellular uptake and retention of (123)I-IIMU were evaluated. Mice inoculated with each cell line were treated with capecitabine for 2 wk, and tumor growth was compared. In vivo distribution studies and SPECT/CT imaging of (123)I-IIMU were performed in inoculated mice.
  
  
  
  In vitro experiments showed a positive relation between TP expression levels and doxifluridine sensitivity. In vitro studies revealed that intracellular uptake and retention of (123)I-IIMU were dependent on TP expression levels. In vivo experiments in inoculated mice showed that (123)I-IIMU accumulation in tumor tissue was in line with TP expression levels and susceptibility to capecitabine treatment. Moreover, SPECT/CT imaging of (123)I-IIMU in tumor-inoculated mice showed that (123)I-IIMU reflects TP expression levels in tumor tissues.
  
  
  
  (123)I-IIMU could be used as an in vivo companion diagnostic for predicting the efficacy of capecitabine treatment.
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kobashi
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan hiroki_matsumoto@nmp.co.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Meike
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okumura
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Sodegaura, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Showa Pharmaceutical University, Machida, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Akizawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan; and.
authors.forename: Kazue
authors.initials: K
authors.lastname: Ohkura
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Nishijima
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo, Japan Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000818:Animals; D000069287:Capecitabine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000072098:Single Photon Emission Computed Tomography Computed Tomography / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000069287:Capecitabine; D015720:5'-Nucleotidase
keywords: companion diagnostics; doxifluridine; single photon emission computed tomography; uracil derivative