title: SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model.
abstract: OBJECTIVE
  Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with (111)In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer.
  
  
  METHODS
  Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of (111)In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples.
  
  
  RESULTS
  Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with (111)In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of (111)In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia.
  
  
  CONCLUSIONS
  Although there are some limitations in evaluating the malignancy of small lung tumors using (111)In-DOTA-c(RGDfK), SPECT with (111)In-DOTA-c(RGDfK) might be a useful non-invasive imaging approach for evaluating the characteristics of lung tumors in mice, thus showing potential for use in humans.
authors.affiliation: Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Akinori
authors.initials: A
authors.lastname: Yanaka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujii
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D001345:Autoradiography; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000473:pathology; D008297:Male; D051379:Mice; D064847:Multimodal Imaging; D009154:Mutation; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D014520:Urethane / Q000494:pharmacology
chemical_list: C532506:111In-DOTA-cyclo(arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D039302:Integrin alphaVbeta3; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D014520:Urethane; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)