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EJNMMI Research
Published in: EJNMMI Research 1/2016

Open Access 01-12-2016 | Original research

Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft

Authors: Naoyuki Ukon, Songji Zhao, Wenwen Yu, Yoichi Shimizu, Ken-ichi Nishijima, Naoki Kubo, Yoshimasa Kitagawa, Nagara Tamaki, Kei Higashikawa, Hironobu Yasui, Yuji Kuge

Published in: EJNMMI Research | Issue 1/2016

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Abstract

Background

Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-3H(N)]-3′-fluoro-3′-deoxythythymidine ([3H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498).
The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [18F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [18F]FLT.

Results

The dynamic pattern of [18F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [18F]FLT phosphorylation (k3) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [18F]FLT forward transport (K1) to reverse transport (k2), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group).

Conclusions

Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
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Metadata
Title
Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft
Authors
Naoyuki Ukon
Songji Zhao
Wenwen Yu
Yoichi Shimizu
Ken-ichi Nishijima
Naoki Kubo
Yoshimasa Kitagawa
Nagara Tamaki
Kei Higashikawa
Hironobu Yasui
Yuji Kuge
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-016-0246-z

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