title: Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.
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.
authors.affiliation: Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.|Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Ukon
authors.affiliation: Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.|Department of Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Tracer Kinetics & Bioanalysis, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.|Department of Oral Diagnosis and Medicine, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.|Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Nishijima
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kubo
authors.affiliation: Department of Oral Diagnosis and Medicine, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Higashikawa
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan. kuge@ric.hokudai.ac.jp.|Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-8638, Japan. kuge@ric.hokudai.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
keywords: 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT); Dynamic PET; Renal cell carcinoma xenograft; Sorafenib; Tumor proliferation