title: Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma.
abstract: BACKGROUND
  (64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is an imaging agent for positron emission tomography (PET) that targets hypoxic tumors. (64)Cu-ATSM is also reported to be a potential agent for internal radiotherapy. In a mouse colon carcinoma (Colon-26) model, we have shown that (64)Cu-ATSM preferentially localizes in intratumoral regions with a high density of CD133(+) cells, which show characteristics of cancer stem cells or cancer stem cell-like cells (collectively referred here as CSCs). In this study, we evaluated the therapeutic effect of (64)Cu-ATSM in relation to CD133 expression using this model.
  
  
  METHODS
  Systemic administration of 37 MBq (64)Cu-ATSM or saline was conducted twice within a 1-week interval to mice bearing 1-week-old Colon-26 tumors (days 0-7). At day 19, tumor size measurement, flow cytometry analysis and experimental lung metastatic assay were performed. The therapeutic effect of (64)Cu-ATSM on sorted CD133(+) and CD133(-) Colon-26 cells was also examined in vitro.
  
  
  RESULTS
  In vivo studies showed that (64)Cu-ATSM treatment inhibited tumor growth. The percentage of CD133(+) cells and metastatic ability in (64)Cu-ATSM treated tumors was decreased compared with that in control animals. In vitro studies demonstrated that (64)Cu-ATSM accumulated in cells under hypoxic conditions and incorporation of (64)Cu-ATSM under hypoxia caused cell death in both CD133(+) and CD133(-) cells in a similar extent.
  
  
  CONCLUSIONS
  (64)Cu-ATSM administration reduced tumor volume as well as the percentage of CD133(+) cells and the metastatic ability of Colon-26 tumors. Together with our data, it is suggested that (64)Cu-ATSM accumulates in regions high in CD133(+) highly tumorigenic cells and kills such regions by radiation, resulting in a decrease of the percentage of CD133(+) cells.
authors.affiliation: Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Ryo
authors.initials: R
authors.lastname: Watanabe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshii
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Asai
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Okazawa
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001692:Biological Transport; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000172:deficiency / Q000378:metabolism*; D013882:Thiosemicarbazones / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000528:radiation effects
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D006023:Glycoproteins; D009942:Organometallic Compounds; D010455:Peptides; C000606024:Prom1 protein, mouse; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)