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

Naoyuki Ukon; Songji Zhao; Wenwen Yu; Yoichi Shimizu; Ken-Ichi Nishijima; Naoki Kubo; Yoshimasa Kitagawa; Nagara Tamaki; Kei Higashikawa; Hironobu Yasui; Yuji Kuge

doi:10.1186/s13550-016-0246-z

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

EJNMMI Res. 2016 Dec;6(1):90. doi: 10.1186/s13550-016-0246-z. Epub 2016 Dec 12.

Authors

Naoyuki Ukon^{1

2}, Songji Zhao^{1

3}, Wenwen Yu^{1

4}, Yoichi Shimizu^{2

5

6}, Ken-Ichi Nishijima^{2

5}, Naoki Kubo^{2

5}, Yoshimasa Kitagawa⁴, Nagara Tamaki⁷, Kei Higashikawa^{2

5}, Hironobu Yasui^{2

5}, Yuji Kuge^{8

9}

Affiliations

¹ Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
² Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.
³ Department of Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
⁴ Department of Oral Diagnosis and Medicine, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
⁵ Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
⁶ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, 060-0812, Japan.
⁷ Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
⁸ Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan. [email protected].
⁹ Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan. [email protected].

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.

Keywords: 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT); Dynamic PET; Renal cell carcinoma xenograft; Sorafenib; Tumor proliferation.