title: Increased intratumoral fluorothymidine uptake levels following multikinase inhibitor sorafenib treatment in a human renal cell carcinoma xenograft model.
abstract: An early identification of the tumor response to sorafenib treatment is indispensable for selecting optimal personalized treatment strategies. However, at present, no reliable predictors are clinically available.18F-fluorothymidine (18F-FLT) positron emission tomography (PET) is used to assess tumor proliferation, since the FLT uptake level reflects thymidine kinase-1 (TK-1) activity. Thus, the present study determined whether FLT was able to evaluate the early tumor response to sorafenib treatment in a human renal cell carcinoma (RCC; A498) xenograft in comparison with the tumor proliferation marker, Ki-67. Mice bearing A498 tumors were assigned to the control and sorafenib-treated groups and the tumor volume was measured every day. [Methyl-3H(N)]-3'-fluoro-3'-deoxythymidine (3H-FLT) was injected 2 h prior to the sacrifice of the mice on days three and seven following the treatment.3H-FLT autoradiography (ARG) and Ki-67 immunohistochemistry (IHC) were performed using adjacent tumor sections. In the visual assessment, the intratumoral3H-FLT uptake level diffusely increased following the treatment, while no significant changes were observed in Ki-67 IHC. The intratumoral3H-FLT uptake levels significantly increased by 2.7- and 2.6-fold on days three and seven following the treatment, while the tumor volume and Ki-67 index did not significantly change. Thus, an increased FLT uptake level was demonstrated following the treatment, which may indicate the suppression of thymidylate synthase (TS) and the compensatory upregulation of TK-1 activity by sorafenib.
authors.affiliation: Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan ; Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, 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: Wenwen
authors.initials: W
authors.lastname: Yu
authors.forename: Chowdhury Nusrat
authors.initials: CN
authors.lastname: Fatema
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Nishijima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamasaki
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
keywords: Ki-67 labeling index; anti-angiogenic therapy; fluorothymidine; positron emission tomography; tumor proliferation