title: A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone].
abstract: Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [62,64Cu] copper-diacetyl-bis[N(4)-methylthio- semicarbazone] (Cu-ATSM), have been used for imaging hypoxic tumors. High accumulation of these tracers in tumors was shown to predict poor prognosis. Both similar and different intratumoral distributions of these PET tracers have been reported with some studies questioning the dependence of the Cu-ATSM accumulation on hypoxia. In the present study, we compared the intratumoral distribution and cellular uptake of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole (FAZA) and Cu-ATSM. Intratumoral distributions of FAZA and Cu-ATSM compared by double tracer autoradiography in xenografts of 8 cancer cell lines and 3 cancer tissue originated spheroids (CTOSs) showed that only a limited overlap was observed between the regions with high levels of FAZA and Cu-ATSM accumulation in all the xenografts. Immunohistochemistry in the regions enriched with FAZA and Cu-ATSM in xenografts demonstrated that pimonidazole adducts were in regions that accumulated high levels of FAZA, while HIF-1α was in areas enriched with either tracer. In addition, we examined the cellular uptake of FAZA and Cu-ATSM at different levels of oxygen concentration in 4 cell lines and revealed that cellular uptake of FAZA was increased with the decrease of oxygen concentration from 20 to 2 and from 2 to 1%, while the Cu-ATSM uptake increased with the decrease of oxygen concentration from 20 to 2%, but did not increase with the decrease from 2 to 1%. Our findings indicate that intratumoral distributions of FAZA and Cu-ATSM were essentially non-overlapping and although hypoxia affects the buildup of both tracers, the accumulation of Cu-ATSM occurred at milder hypoxia compared to the conditions required for the accumulation of FAZA. Therefore, accumulation levels of FAZA and Cu-ATSM may be considered as independent biomarkers.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Winn
authors.initials: W
authors.lastname: Aung
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Sumitaka
authors.initials: S
authors.lastname: Hasegawa
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Endo
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D058948:Cell Tracking; D056831:Coordination Complexes; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D009593:Nitroimidazoles / Q000737:chemistry* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011859:Radiography; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D056831:Coordination Complexes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18