title: Biological characteristics of intratumoral [F-18]‑fluoromisonidazole             distribution in a rodent model of glioma.
abstract: Accurate imaging to identify hypoxic regions in tumors is key for radiotherapy planning. [F-18]‑fluoro-misonidazole ([F-18]-FMISO) is widely used for tumor hypoxia imaging and has the potential to optimize radiotherapy planning. However, the biological characteristics of intratumoral [F-18]-FMISO distribution have not yet been fully investigated. In hypoxic cells, the hypoxia-inducible factor-1 (HIF-1) target proteins that induce cellular proliferation and glucose metabolism, glucose transporter-1 (Glut-1) and hexokinase-II (HK-II), are upregulated. In this study, we determined the intratumoral distribution of [F-18]-FMISO by autoradiography (ARG) and compared it with pimonidazole uptake, expression of Glut-1, tumor proliferative activity (Ki-67 index) and glucose metabolism ([C-14]2-fluoro-2-deoxy-D-glucose uptake; [C-14]-FDG) in a glioma rat model. Five C6 glioma‑bearing rats were injected with [F-18]-FMISO and [C-14]-FDG. After 90 min, the rats were injected with pimonidazole and 60 min later, the rats were sacrificed and tumor tissues were sectioned into slices. The adjacent slices were used for ARG and immunohistochemical (IHC) analyses of pimonidazole, Glut-1 and Ki-67. [F-18]-FMISO ARG images were divided into regions of high [F-18]-FMISO uptake (FMISO+) and low [F-18]-FMISO uptake (FMISO-). Pimonidazole and Glut-1 expression levels, Ki-67 index and [C-14]-FDG distribution were evaluated in the regions of interest (ROIs) placed on FMISO+ and FMISO-. [F-18]-FMISO distribution was generally consistent with pimonidazole distribution. The percentage of positively stained areas (% positive) of Glut-1 in FMISO+ was significantly higher compared to FMISO- (24 ± 8% in FMISO+ and 9 ± 4% in FMISO-; P<0.05). There were no significant differences in Ki-67 index and [C-14]-FDG uptake between FMISO+ and FMISO- (for Ki-67, 10 ± 5% in FMISO+ and 12 ± 5% in FMISO-, P=ns; for [C-14]-FDG, 1.4 ± 0.3% ID/g/kg in FMISO+ and 1.3 ± 0.3% ID/g/kg in FMISO-, P = ns). Intratumoral [F-18]-FMISO distribution reflected tumor hypoxia and expression of the hypoxia‑related gene product Glut-1; it did not, however, reflect tumor proliferation or glucose metabolism. Our findings help elucidate the biological characteristics of intratumoral [F-18]-FMISO distribution that are relevant to radiotherapy planning.
authors: Central Institute of Isotope Science, Hokkaido University, Sapporo,                     Japan.
authors: Toshiyuki
authors: T
authors: Hatano
authors: Songji
authors: S
authors: Zhao
authors: Yan
authors: Y
authors: Zhao
authors: Ken-Ichi
authors: K
authors: Nishijima
authors: Norihito
authors: N
authors: Kuno
authors: Hiroko
authors: H
authors: Hanzawa
authors: Takeshi
authors: T
authors: Sakamoto
authors: Nagara
authors: N
authors: Tamaki
authors: Yuji
authors: Y
authors: Kuge
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport; D001932:Brain Neoplasms / Q000175:diagnosis*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005910:Glioma / Q000175:diagnosis*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006593:Hexokinase / Q000096:biosynthesis; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen; D008297:Male; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D009593:Nitroimidazoles / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D019394:Ki-67 Antigen; D009593:Nitroimidazoles; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; C033815:pimonidazole; D008920:Misonidazole; D006593:Hexokinase; D005947:Glucose