title: Evaluation of changes in the tumor microenvironment after sorafenib             therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in             renal cell carcinoma.
abstract: The mechanistic dissociation of 'tumor starvation' versus 'vascular normalization'             following anti-angiogenic therapy is a subject of intense controversy in the field             of experimental research. In addition, accurately evaluating changes of the tumor             microenvironment after anti-angiogenic therapy is important for optimizing treatment             strategy. Sorafenib has considerable anti-angiogenic effects that lead to tumor             starvation and induce tumor hypoxia in the highly vascularized renal cell carcinoma             (RCC) xenografts. 18F-fluoromisonidazole (18F‑FMISO) is a proven hypoxia imaging             probe. Thus, to clarify early changes in the tumor microenvironment following             anti-angiogenic therapy and whether 18F-FMISO imaging can detect those changes,             we evaluated early changes in the tumor microenvironment after sorafenib treatment             in an RCC xenograft by sequential histological analysis and 18F-FMISO autoradiography             (ARG). A human RCC xenograft (A498) was established in nude mice, for histological             studies and ARG, and further assigned to the control and sorafenib-treated groups             (80 mg/kg, per os). Mice were sacrificed on Days 1, 2, 3 and 7 in the histological             study, and on Days 3 and 7 in ARG after sorafenib treatment. Tumor volume was             measured every day. 18F-FMISO and pimonidazole were injected intravenously 4 and             2 h before sacrifice, respectively. Tumor sections were stained with hematoxylin             and eosin and immunohistochemically with pimonidazole and CD31. Intratumoral 18F-FMISO             distribution was quantified in ARG. Tumor volume did not significantly change             on Day 7 after sorafenib treatment. In the histological study, hypoxic fraction             significantly increased on Day 2, mean vessel density significantly decreased             on Day 1 and necrosis area significantly increased on Day 2 after sorafenib treatment.             Intratumoral 18F-FMISO distribution significantly increased on Days 3 (10.2-fold,             p<0.01) and 7 (4.1-fold, p<0.01) after sorafenib treatment. The sequential             histological evaluation of the tumor microenvironment clarified tumor starvation             in A498 xenografts treated with sorafenib. 18F-FMISO hypoxia imaging confirmed             the tumor starvation. 18F-FMISO PET may contribute to determine an optimum treatment             protocol after anti-angiogenic therapy.
authors.affiliation: Laboratory of Veterinary Internal Medicine, Graduate School of                     Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Murakami
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Nusrat Fatema
authors.initials: NF
authors.lastname: Chowdhury
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yu
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Nishijima
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019275:Radiopharmaceuticals; D000077157:Sorafenib; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D009536:Niacinamide; D008920:Misonidazole; D000077157:Sorafenib