Increased intratumoral fluorothymidine uptake levels following multikinase inhibitor sorafenib treatment in a human renal cell carcinoma xenograft model

Murakami,Masahiro; Zhao,Songji; Zhao,Yan; Yu,Wenwen; Fatema,Chowdhury Nusrat; Nishijima,Ken‑Ichi; Yamasaki,Masahiro; Takiguchi,Mitsuyoshi; Tamaki,Nagara; Kuge,Yuji

doi:10.3892/ol.2013.1459

Increased intratumoral fluorothymidine uptake levels following multikinase inhibitor sorafenib treatment in a human renal cell carcinoma xenograft model

Authors:
- Masahiro Murakami
- Songji Zhao
- Yan Zhao
- Wenwen Yu
- Chowdhury Nusrat Fatema
- Ken‑Ichi Nishijima
- Masahiro Yamasaki
- Mitsuyoshi Takiguchi
- Nagara Tamaki
- Yuji Kuge
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Affiliations: 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, Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan, Central Institute of Isotope Science, Hokkaido University, Sapporo, Hokkaido 060‑0815, Japan
Published online on: July 12, 2013 https://doi.org/10.3892/ol.2013.1459
Pages: 667-672

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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 intratumoral 3H‑FLT uptake level diffusely increased following the treatment, while no significant changes were observed in Ki‑67 IHC. The intratumoral 3H‑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.

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