Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.
Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.
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DOI：
10.1186/s13550-016-0246-z
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发表时间：
2016-12
期刊：
影响因子：
3.2
通讯作者：
Kuge Y
中科院分区：
文献类型：
--
作者：
Ukon N;Zhao S;Yu W;Shimizu Y;Nishijima KI;Kubo N;Kitagawa Y;Tamaki N;Higashikawa K;Yasui H;Kuge Y
索拉非尼是一种口服多激酶抑制剂，具有抗增殖和抗血管生成活性，对肾细胞癌（RCC）有治疗效果。最近，我们评估了使用[甲基-3H(N)]-3 ' -氟-3 ' -脱氧胸腺嘧啶（[3H]FLT）在RCC异种移植中治疗索拉非尼的肿瘤反应。与我们的预期相反，治疗后肿瘤中的FLT水平显著升高。在本研究中，为了阐明FLT水平升高的原因，对携带RCC异种移植物的小鼠进行了动态3 ' -[18F]氟-3 ' -脱氧胸腺嘧啶（[18F]FLT）正电子发射断层扫描（PET）和动力学研究（A498）。在裸鼠体内建立A498异种移植物，将小鼠分为对照组（n = 5）和治疗组（n = 5）。治疗组小鼠口服索拉非尼（20 mg/kg/d, p.o.），每日1次，连用3 d。治疗24小时后，采用小动物PET进行动态[18F]FLT PET。三维感兴趣区域（roi）被手动定义为肿瘤。采用三室模型拟合，利用肿瘤中的时间活性曲线（TAC）和[18F]FLT的血液清除率来估计四个速率常数。治疗后肿瘤内[18F]FLT水平的动态格局发生明显改变。治疗组[18F]FLT磷酸化速率常数（k3）（0.111±0.027 [1/min]）明显高于对照组（0.082±0.009 [1/min]）。两组间的分布体积、[18F]FLT正向转运（K1）与反向转运（k2）之比（对照组为0.556±0.073,0.641±0.052 [mL/g]）无显著变化。我们的动态PET研究表明，移植RCC的小鼠在接受索拉非尼治疗后，FLT水平的增加可能是由肿瘤中FLT的磷酸化引起的。采用动力学模型的动态PET研究可以更好地理解肿瘤对治疗反应的生化过程。
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. 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). 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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影响因子：
5.2
作者：
Murakami M;Zhao S;Zhao Y;Chowdhury NF;Yu W;Nishijima K;Takiguchi M;Tamaki N;Kuge Y
通讯作者：
Kuge Y
影响因子：
2.9
作者：
Murakami M;Zhao S;Zhao Y;Yu W;Fatema CN;Nishijima KI;Yamasaki M;Takiguchi M;Tamaki N;Kuge Y
通讯作者：
Kuge Y
DOI：
10.1158/1078-0432.ccr-11-1677
发表时间：
2011-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liu G;Jeraj R;Vanderhoek M;Perlman S;Kolesar J;Harrison M;Simoncic U;Eickhoff J;Carmichael L;Chao B;Marnocha R;Ivy P;Wilding G
通讯作者：
Wilding G
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
2.6
作者：
Rendl G;Rettenbacher L;Holzmannhofer J;Datz L;Hauser-Kronberger C;Fastner G;Öfner D;Sedlmayer F;Pirich C
通讯作者：
Pirich C