~(18)F-FLT、~(18)F-FDG双示踪剂评价肺腺癌及肺大细胞癌放疗疗效的基础研究
|
摘要
背景:肺癌是最常见的恶性肿瘤之一,近年来肺癌的发病率和死亡率上升显著,放射治疗在肺癌的治疗中占有极其重要的地位,PET是近年来迅速发展起来的影像技术,给肺癌的诊断和分期,尤其在肺癌放疗后的疗效评价带来巨大帮助。本文分两个部分,第一部分系统分析~(18)F-FLT、~(18)F-FDG双示踪评价肺腺癌及肺大细胞癌细胞株外照射后~(18)F-FLT及~(18)F-FDG摄取,第二部分研究~(18)F-FLT及~(18)F_FDG在肺腺癌及肺大细胞癌动物模型放疗后的生物分布及PET显像。
目的:1、研究人肺A549腺癌细胞株及人肺95-D大细胞癌细胞株在接受放射线照射后对3'-脱氧-3'-~(18)F-氟代胸苷(~(18)F-FLT)及~(18)F-氟代脱氧葡萄糖(~(18)F-FDG)的摄取变化情况。2、研究~(18)F-FLT和~(18)F-FDG在荷肺腺癌及荷肺大细胞癌小鼠的生物分布和MicroPET显像。3、评价~(18)F-FLT和~(18)F-FDG在监测肺腺癌及肺大细胞癌放疗疗效中的作用。4、评价肺腺癌及肺大细胞癌在放疗前后~(18)F-FLT、~(18)F-FDG生物分布和MicroPET显像差别。
方法:1、细胞学研究:(1)取生长旺盛的A549肺腺癌细胞,调节细胞浓度至5×10~4/ml,分组加入6孔培养板,每孔200uL。每份培养基中加入~(18)F-FLT或~(18)F-FDG50kBq,用6Mv X线等中心单次照射500cGy、1000cGy和2000cGy。放疗后6小时、12小时、24小时和72小时,用井形γ计数器测定细胞悬液放射性活度。(2)取生长旺盛的人肺95-D大细胞癌细胞株,调节细胞浓度至5×10~4/ml,分组加入6孔培养板,每孔200uL。每份培养基中加入~(18)F-FLT或~(18)F-FDG50kBq,用6Mv X线等中心单次照射500cGy、1000cGy和2000cGy。放疗后6小时、12小时、24小时和72小时,用井形γ计数器测定细胞悬液放射性活度。
2、动物模型研究:(1)采用随机配对分组将荷肺腺癌小鼠分为FLT组和FDG组,每组3只。两组分别于注射~(18)F-FLT和~(18)F-FDG后60min进行PET显像和生物分布测定。(2)将荷肺大细胞癌小鼠分为FLT组和FDG组,每组3只。两组分别于注射。~(18)F-FLT和~(18)F-FDG后60min进行PET显像和生物分布测定。(3) 18只荷肺腺癌小鼠随机分为~(18)F-FLT和~(18)F-FDG两组,各组又随机配对分为A组、B组、C组,每组3只。A组为对照组,未进行任何治疗;B组于实验前1天采用异氟醚麻醉后,固定于直线加速器下,对小鼠肿瘤部位进行放疗,单次剂量2000cGy,能量6MV,射线类型为X线;C组于实验前2天同样对小鼠肿瘤部位进行放疗,操作方法及放疗剂量同B组。经小鼠尾静脉注入~(18)F-FLT和~(18)F-FDG后行MicroPET显像,并处死小鼠取各器官用井形探测仪测定生物分布。(4) 18只荷肺大细胞癌小鼠随机分为~(18)F-FLT和~(18)F-FDG两组,各组又随机配对分为A组、B组、C组,每组3只。A组为对照组,未进行任何治疗;B组于实验前1天采用异氟醚麻醉后,固定于直线加速器下,对小鼠肿瘤部位进行放疗,单次剂量2000cGy,能量6MV,射线类型为X线;C组于实验前2天同样对小鼠肿瘤部位进行放疗,操作方法及放疗剂量同B组。经小鼠尾静脉注入。~(18)F-FLT和~(18)F-FDG后行MicroPET显像,并处死小鼠取各器官用井形探测仪测定生物分布。
结果:1、细胞学研究:(1)人肺A549腺癌细胞株接受三种剂量照射后不同时间~(18)F-FLT和~(18)F-FDG摄取变化情况,可见1000cGy组6h、12h及2000cGy组各时间点摄取均降低。三种不同剂量照射后组间~(18)F-FLT摄取比较,500cGy组与1000cGy组有显著差别(p＜0.05);500cGy组与2000cGy组有显著差别(p＜0.05)。(2)人肺95-D大细胞癌细胞株~(18)F-FLT摄取变化情况,可见500cGy组24h、72h摄取明显增高(138±7%,p＜0.05;141±5%,p＜0.05)。1000cGy及2000cGy组6h、12h、24h、72h ~(18)F-FLT摄取明显降低。三种不同剂量照射后组间~(18)F-FLT摄取比较,500cGy组与1000cGy组有显著差别(p＜0.05);500cGy组与2000cGy组有显著差别(p＜0.05);1000cGy组与2000cGy组无显著差别(p＞0.05)。(3)外照射500cGy后24h、72h肺大细胞癌95-D细胞株~(18)F-FLT摄取明显高于肺腺癌A549细胞株(111±6%,141±5%,p＜0.05:107±8%,138±7%,p＜0.05)。
2、动物模型研究:(1)荷肺腺癌小鼠的生物分布研究中发现,肿瘤部位~(18)F-FLT及~(18)F-FDG摄取较高,肿瘤对肌肉及肺的T/NT比值均大于2,~(18)F_FLT、~(18)F-FDG PET对肿瘤显像清晰。(2)荷肺大细胞癌小鼠的生物分布研究中发现,肿瘤部位~(18)F-FLT及lSF-FDG摄取较高,肿瘤对肌肉及肺的T/NT比值均大于2,~(18)F-FLT、及~(18)F-FDG PET对肿瘤显像清晰。(3)两种肿瘤间摄取~(18)F-FLT的肿瘤/肺及肿瘤/肌肉均有显著差异(P＜0.05),两种肿瘤间摄取~(18)F-FDG的肿瘤/肺有显著差异(P＜0.05),而肿瘤/肌肉值在两种肿瘤间无明显差异(P＞0.05)。~(18)F-FLT、~(18)F-FDG PET显像显示两种肿瘤间无明显差别(P＞0.05)。(4)放疗后肺腺癌~(18)F-FLT摄取较对照组明显降低(P＜0.05),而~(18)F-FDG摄取变化不明显。PET显像FLT组在放疗后24h、48h后T/NT值明显降低且与放疗前对比有明显差异(P＜0.05)。FDG组则无明显差异。(5)放疗后肺大细胞癌~(18)F-FLT摄取较对照组明显降低(1.33±0.27%和0.58±0.08%,p＜0.05),FDG组中C组(放疗后48h)与A组(放疗前)比较有显著性差异(P＜0.05)。PET显像FLT组在放疗后24h、48h后T/NT值明显降低且与放疗前对比有明显差异(P＜0.05),FDG放疗组的48h与放疗前对比有明显差异(P＜0.05)。(6)肺腺癌及肺大细胞癌间放疗后~(18)F-FDG摄取在24h时有统计学差异(P＜0.05);~(18)F-FLT在放疗后24h、48h摄取均有统计学差异(P＜0.05)。放疗后PET显像大细胞癌T/NT值较腺癌低,而且T/NT值降低幅度也比腺癌大,但二者无统计学意义(P＞0.05)。
结论:研究结果表明,~(18)F-FLT可被肺部恶性肿瘤摄取。对肿瘤的特异度高于~(18)F-FDG。有效放疗引起的~(18)F-FLT摄取变化较~(18)F-FDG灵敏,放疗后~(18)F-FLT摄取降低较~(18)F-FDG明显,因而~(18)F-FLT是一种监测肿瘤治疗疗效的有前途的示踪剂。同时,~(18)F-FLT在肺腺癌及肺大细胞癌摄取研究表明,大细胞癌摄取明显高于肺腺癌,有效放射治疗后体内生物分布仍然有此趋势,因而~(18)F-FLT有望在肺腺癌及肺大细胞癌的诊断鉴别和放疗后疗效评价方面会有所帮助。总之,细胞学、动物学研究都表明,~(18)F-FLT对肿瘤特异性、对有效治疗的敏感性、与细胞增殖的相关性都高于~(18)F-FDG,是一种具有发展前景的PET示踪剂。
Background:Lung cancer is one of the most familiar malignant tumors in the world.The incidence rate and death rate increased significantly recent years, Radiotherapy plays a very important role in the treatment of lung cancer.Positron emission tomography(PET) is a rapidly developing new imaging technique in the diagnosis and staging of lung cancer,especially in the evaluation for monitoring lung cancer response to radiotherapy.There are two parts in this study.In PartⅠ, systematic review the biodistribution of ~(18)F-FLT and ~(18)F-FDG in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after the irradiation.In Part 2,the ~(18)F-FLT and ~(18)F-FDG biodistribution and PET imaging of lung adenocarcinoma,lung large cell carcinoma in murine model were investigated.
Objective:1.The biodistribution of 3'-deoxy-3'-~(18)F-fluorothy- midine(~(18)F-FLT) and 2-deoxy-2-~(18)F-fluoro-D-glucose(~(18)F-FDG) in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after irradiation are investigated.2.The biodistribution and positron emission tomography(PET) imaging of ~(18)F-FLT and ~(18)F-FDG in routine model of lung adenocarcinoma and lung large cell carcinoma are investigated.3.The use of ~(18)F-FLT and ~(18)F-FDG for monitoring lung adenocarcinoma and lung large cell carcinoma response to radiotherapy are evaluate.4.The biodistribution and positron emission tomography imaging difference between lung adenocarcinoma and lung large cell carcinoma are evaluated.
Methods:Cytological Experiment:1.Lung adenocarcinoma cells line(A549) were treated with 6Mv X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12,24 and 72 hours later,the cell concentration were regulated to 5× 10~4/ml,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.2.Lung large cell carcinoma cells line(95-D) were treated with 6My X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12, 24 and 72 hours later,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.
Animal Experiment:1.6 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG), The bodistribution of mice was measured with well-gamma detector at 60min, after injection by tail veins.The MicroPET imaging was performed at 60min.2.6 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),The bodistribution of mice was measured with well-gamma detector at 60min,after injection by tail veins.The MicroPET imaging was performed at 60min.3.18 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection,bodistribution and PET imaging were performed.4.18 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection, bodistribution and PET imaging were performed.
Results:Cytological Experiment:1.~(18)F-FLT uptake of lung adenocarcinoma cell line(AS49) after irradia- tion decreased at 6,12 hour of 1000cGy group and 6, 12,24,72 hour of 2000cGy group.There are significant differences between 500cGy and 1000cGy group,500cGy and 2000cGy group.2.~(18)F-FLT uptake of lung large cell carcinoma cell line(95-D) after irradiation increased at 24,72 hour of 500cGy group and decreased at 6,12,24,72 hour of 1000cGy and 2000cGy group.There are signifi- cant differences between 500cGy and 1000cGy group, 500cGy and 2000cGy group.3.~(18)F-FLT uptake of lung large cell carcinoma 95-D cell line was signifi- cantly higher than that of lung adenocarcinoma A549 cell line(111±6%,141±5%,p＜0.05;107±8%,138±7%,p＜0.05).
Animal Experiment:1.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.2.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.3.There was statistically difference between the two tumors at the tumor/muscle and tumor/lung value in ~(18)F-FLT and tumor/lung value in ~(18)F-FDG, but no statistically difference at the tumor/muscle value in ~(18)F-FDG.4.~(18)F-FLT uptake in murine model of lung adenocarcinoma after irradiation was significantly lower than that of control group(0.71±0.08%和0.33±0.07%,p＜0.05).~(18)F-FLT PET imaging T/NT value was significantly lower than that of control group.But there was no statistically significant in ~(18)F-FDG group.5.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irradiation was significantly lower than that of control group(1.33±0.27%和0.58±0.08%,p＜0.05);~(18)F-FDG uptake after irradiation 48h was significantly lower than that of control group. PET imaging after radiotherapy,the T/NT value of FLT group was significantly lower than the control group after 24h,48h(P＜0.05).FLT group was significantly lower than the control group after 48h(P＜0.05).6.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irridiation was significantly higher than that of lung adenocarcinoma;and there was statistically difference in 24h after irridiation of ~(18)F-FDG uptake between the two tumors.MicroPET imaging showed that there was no statistically significant between the two tumors. Conclusions:Our experimental Studies shows that the uptake of ~(18)F-FLT in pulmonary malignant tissues is higher than that in normal tissues,thus the pulmonary neoplasm can be identified accurately with PET imaging.The decrease in tumor ~(18)F-FLT uptake after radiotherapy was more pronounced than that of ~(18)F-FDG.Therefore,~(18)F-FLT is a promising PET tracer for monitoring response to therapy in oncology.At the same time,~(18)F-FLT uptake studies about lung adenocarcinoma and lung large cell carcinoma have shown that uptake of large cell carcinoma was significantly higher than that of lung adenocarcinoma,there is still such a trend after radiotherapy.So ~(18)F-FLT is expected to be helpful to the differential diagnosis of lung adenocarcinoma and lung large cell carcinoma and efficacy evaluation after radiotherapy.PET imaging with ~(18)F-FLT represents a useful supplement to ~(18)F-FDG in assessing the malignancy.~(18)F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ~(18)F-FDG and might be more useful as a selective biomarker for tumor proliferation.
目的:1、研究人肺A549腺癌细胞株及人肺95-D大细胞癌细胞株在接受放射线照射后对3'-脱氧-3'-~(18)F-氟代胸苷(~(18)F-FLT)及~(18)F-氟代脱氧葡萄糖(~(18)F-FDG)的摄取变化情况。2、研究~(18)F-FLT和~(18)F-FDG在荷肺腺癌及荷肺大细胞癌小鼠的生物分布和MicroPET显像。3、评价~(18)F-FLT和~(18)F-FDG在监测肺腺癌及肺大细胞癌放疗疗效中的作用。4、评价肺腺癌及肺大细胞癌在放疗前后~(18)F-FLT、~(18)F-FDG生物分布和MicroPET显像差别。
方法:1、细胞学研究:(1)取生长旺盛的A549肺腺癌细胞,调节细胞浓度至5×10~4/ml,分组加入6孔培养板,每孔200uL。每份培养基中加入~(18)F-FLT或~(18)F-FDG50kBq,用6Mv X线等中心单次照射500cGy、1000cGy和2000cGy。放疗后6小时、12小时、24小时和72小时,用井形γ计数器测定细胞悬液放射性活度。(2)取生长旺盛的人肺95-D大细胞癌细胞株,调节细胞浓度至5×10~4/ml,分组加入6孔培养板,每孔200uL。每份培养基中加入~(18)F-FLT或~(18)F-FDG50kBq,用6Mv X线等中心单次照射500cGy、1000cGy和2000cGy。放疗后6小时、12小时、24小时和72小时,用井形γ计数器测定细胞悬液放射性活度。
2、动物模型研究:(1)采用随机配对分组将荷肺腺癌小鼠分为FLT组和FDG组,每组3只。两组分别于注射~(18)F-FLT和~(18)F-FDG后60min进行PET显像和生物分布测定。(2)将荷肺大细胞癌小鼠分为FLT组和FDG组,每组3只。两组分别于注射。~(18)F-FLT和~(18)F-FDG后60min进行PET显像和生物分布测定。(3) 18只荷肺腺癌小鼠随机分为~(18)F-FLT和~(18)F-FDG两组,各组又随机配对分为A组、B组、C组,每组3只。A组为对照组,未进行任何治疗;B组于实验前1天采用异氟醚麻醉后,固定于直线加速器下,对小鼠肿瘤部位进行放疗,单次剂量2000cGy,能量6MV,射线类型为X线;C组于实验前2天同样对小鼠肿瘤部位进行放疗,操作方法及放疗剂量同B组。经小鼠尾静脉注入~(18)F-FLT和~(18)F-FDG后行MicroPET显像,并处死小鼠取各器官用井形探测仪测定生物分布。(4) 18只荷肺大细胞癌小鼠随机分为~(18)F-FLT和~(18)F-FDG两组,各组又随机配对分为A组、B组、C组,每组3只。A组为对照组,未进行任何治疗;B组于实验前1天采用异氟醚麻醉后,固定于直线加速器下,对小鼠肿瘤部位进行放疗,单次剂量2000cGy,能量6MV,射线类型为X线;C组于实验前2天同样对小鼠肿瘤部位进行放疗,操作方法及放疗剂量同B组。经小鼠尾静脉注入。~(18)F-FLT和~(18)F-FDG后行MicroPET显像,并处死小鼠取各器官用井形探测仪测定生物分布。
结果:1、细胞学研究:(1)人肺A549腺癌细胞株接受三种剂量照射后不同时间~(18)F-FLT和~(18)F-FDG摄取变化情况,可见1000cGy组6h、12h及2000cGy组各时间点摄取均降低。三种不同剂量照射后组间~(18)F-FLT摄取比较,500cGy组与1000cGy组有显著差别(p＜0.05);500cGy组与2000cGy组有显著差别(p＜0.05)。(2)人肺95-D大细胞癌细胞株~(18)F-FLT摄取变化情况,可见500cGy组24h、72h摄取明显增高(138±7%,p＜0.05;141±5%,p＜0.05)。1000cGy及2000cGy组6h、12h、24h、72h ~(18)F-FLT摄取明显降低。三种不同剂量照射后组间~(18)F-FLT摄取比较,500cGy组与1000cGy组有显著差别(p＜0.05);500cGy组与2000cGy组有显著差别(p＜0.05);1000cGy组与2000cGy组无显著差别(p＞0.05)。(3)外照射500cGy后24h、72h肺大细胞癌95-D细胞株~(18)F-FLT摄取明显高于肺腺癌A549细胞株(111±6%,141±5%,p＜0.05:107±8%,138±7%,p＜0.05)。
2、动物模型研究:(1)荷肺腺癌小鼠的生物分布研究中发现,肿瘤部位~(18)F-FLT及~(18)F-FDG摄取较高,肿瘤对肌肉及肺的T/NT比值均大于2,~(18)F_FLT、~(18)F-FDG PET对肿瘤显像清晰。(2)荷肺大细胞癌小鼠的生物分布研究中发现,肿瘤部位~(18)F-FLT及lSF-FDG摄取较高,肿瘤对肌肉及肺的T/NT比值均大于2,~(18)F-FLT、及~(18)F-FDG PET对肿瘤显像清晰。(3)两种肿瘤间摄取~(18)F-FLT的肿瘤/肺及肿瘤/肌肉均有显著差异(P＜0.05),两种肿瘤间摄取~(18)F-FDG的肿瘤/肺有显著差异(P＜0.05),而肿瘤/肌肉值在两种肿瘤间无明显差异(P＞0.05)。~(18)F-FLT、~(18)F-FDG PET显像显示两种肿瘤间无明显差别(P＞0.05)。(4)放疗后肺腺癌~(18)F-FLT摄取较对照组明显降低(P＜0.05),而~(18)F-FDG摄取变化不明显。PET显像FLT组在放疗后24h、48h后T/NT值明显降低且与放疗前对比有明显差异(P＜0.05)。FDG组则无明显差异。(5)放疗后肺大细胞癌~(18)F-FLT摄取较对照组明显降低(1.33±0.27%和0.58±0.08%,p＜0.05),FDG组中C组(放疗后48h)与A组(放疗前)比较有显著性差异(P＜0.05)。PET显像FLT组在放疗后24h、48h后T/NT值明显降低且与放疗前对比有明显差异(P＜0.05),FDG放疗组的48h与放疗前对比有明显差异(P＜0.05)。(6)肺腺癌及肺大细胞癌间放疗后~(18)F-FDG摄取在24h时有统计学差异(P＜0.05);~(18)F-FLT在放疗后24h、48h摄取均有统计学差异(P＜0.05)。放疗后PET显像大细胞癌T/NT值较腺癌低,而且T/NT值降低幅度也比腺癌大,但二者无统计学意义(P＞0.05)。
结论:研究结果表明,~(18)F-FLT可被肺部恶性肿瘤摄取。对肿瘤的特异度高于~(18)F-FDG。有效放疗引起的~(18)F-FLT摄取变化较~(18)F-FDG灵敏,放疗后~(18)F-FLT摄取降低较~(18)F-FDG明显,因而~(18)F-FLT是一种监测肿瘤治疗疗效的有前途的示踪剂。同时,~(18)F-FLT在肺腺癌及肺大细胞癌摄取研究表明,大细胞癌摄取明显高于肺腺癌,有效放射治疗后体内生物分布仍然有此趋势,因而~(18)F-FLT有望在肺腺癌及肺大细胞癌的诊断鉴别和放疗后疗效评价方面会有所帮助。总之,细胞学、动物学研究都表明,~(18)F-FLT对肿瘤特异性、对有效治疗的敏感性、与细胞增殖的相关性都高于~(18)F-FDG,是一种具有发展前景的PET示踪剂。
Background:Lung cancer is one of the most familiar malignant tumors in the world.The incidence rate and death rate increased significantly recent years, Radiotherapy plays a very important role in the treatment of lung cancer.Positron emission tomography(PET) is a rapidly developing new imaging technique in the diagnosis and staging of lung cancer,especially in the evaluation for monitoring lung cancer response to radiotherapy.There are two parts in this study.In PartⅠ, systematic review the biodistribution of ~(18)F-FLT and ~(18)F-FDG in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after the irradiation.In Part 2,the ~(18)F-FLT and ~(18)F-FDG biodistribution and PET imaging of lung adenocarcinoma,lung large cell carcinoma in murine model were investigated.
Objective:1.The biodistribution of 3'-deoxy-3'-~(18)F-fluorothy- midine(~(18)F-FLT) and 2-deoxy-2-~(18)F-fluoro-D-glucose(~(18)F-FDG) in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after irradiation are investigated.2.The biodistribution and positron emission tomography(PET) imaging of ~(18)F-FLT and ~(18)F-FDG in routine model of lung adenocarcinoma and lung large cell carcinoma are investigated.3.The use of ~(18)F-FLT and ~(18)F-FDG for monitoring lung adenocarcinoma and lung large cell carcinoma response to radiotherapy are evaluate.4.The biodistribution and positron emission tomography imaging difference between lung adenocarcinoma and lung large cell carcinoma are evaluated.
Methods:Cytological Experiment:1.Lung adenocarcinoma cells line(A549) were treated with 6Mv X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12,24 and 72 hours later,the cell concentration were regulated to 5× 10~4/ml,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.2.Lung large cell carcinoma cells line(95-D) were treated with 6My X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12, 24 and 72 hours later,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.
Animal Experiment:1.6 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG), The bodistribution of mice was measured with well-gamma detector at 60min, after injection by tail veins.The MicroPET imaging was performed at 60min.2.6 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),The bodistribution of mice was measured with well-gamma detector at 60min,after injection by tail veins.The MicroPET imaging was performed at 60min.3.18 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection,bodistribution and PET imaging were performed.4.18 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection, bodistribution and PET imaging were performed.
Results:Cytological Experiment:1.~(18)F-FLT uptake of lung adenocarcinoma cell line(AS49) after irradia- tion decreased at 6,12 hour of 1000cGy group and 6, 12,24,72 hour of 2000cGy group.There are significant differences between 500cGy and 1000cGy group,500cGy and 2000cGy group.2.~(18)F-FLT uptake of lung large cell carcinoma cell line(95-D) after irradiation increased at 24,72 hour of 500cGy group and decreased at 6,12,24,72 hour of 1000cGy and 2000cGy group.There are signifi- cant differences between 500cGy and 1000cGy group, 500cGy and 2000cGy group.3.~(18)F-FLT uptake of lung large cell carcinoma 95-D cell line was signifi- cantly higher than that of lung adenocarcinoma A549 cell line(111±6%,141±5%,p＜0.05;107±8%,138±7%,p＜0.05).
Animal Experiment:1.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.2.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.3.There was statistically difference between the two tumors at the tumor/muscle and tumor/lung value in ~(18)F-FLT and tumor/lung value in ~(18)F-FDG, but no statistically difference at the tumor/muscle value in ~(18)F-FDG.4.~(18)F-FLT uptake in murine model of lung adenocarcinoma after irradiation was significantly lower than that of control group(0.71±0.08%和0.33±0.07%,p＜0.05).~(18)F-FLT PET imaging T/NT value was significantly lower than that of control group.But there was no statistically significant in ~(18)F-FDG group.5.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irradiation was significantly lower than that of control group(1.33±0.27%和0.58±0.08%,p＜0.05);~(18)F-FDG uptake after irradiation 48h was significantly lower than that of control group. PET imaging after radiotherapy,the T/NT value of FLT group was significantly lower than the control group after 24h,48h(P＜0.05).FLT group was significantly lower than the control group after 48h(P＜0.05).6.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irridiation was significantly higher than that of lung adenocarcinoma;and there was statistically difference in 24h after irridiation of ~(18)F-FDG uptake between the two tumors.MicroPET imaging showed that there was no statistically significant between the two tumors. Conclusions:Our experimental Studies shows that the uptake of ~(18)F-FLT in pulmonary malignant tissues is higher than that in normal tissues,thus the pulmonary neoplasm can be identified accurately with PET imaging.The decrease in tumor ~(18)F-FLT uptake after radiotherapy was more pronounced than that of ~(18)F-FDG.Therefore,~(18)F-FLT is a promising PET tracer for monitoring response to therapy in oncology.At the same time,~(18)F-FLT uptake studies about lung adenocarcinoma and lung large cell carcinoma have shown that uptake of large cell carcinoma was significantly higher than that of lung adenocarcinoma,there is still such a trend after radiotherapy.So ~(18)F-FLT is expected to be helpful to the differential diagnosis of lung adenocarcinoma and lung large cell carcinoma and efficacy evaluation after radiotherapy.PET imaging with ~(18)F-FLT represents a useful supplement to ~(18)F-FDG in assessing the malignancy.~(18)F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ~(18)F-FDG and might be more useful as a selective biomarker for tumor proliferation.
引文
1.Tyldesley S,Boyd C,Schulze K,et al.Estimating the need for radiotherapy for lung cancer:An evidence-based,epidemiologic approach[J].Int J Radiat Oncol Biol Phys,2001,49:973-985.
2.Chien CR,Chen SW,Hsieh CY,et al.Intra-thoracic failure pattern and survival status following 3D conformal radiotherapy for non-small cell lung cancer:a preliminary report[J].Jpn J Clin Oncol,2001,31(2):55-60.
3.Schiepers C,Haustermans K,Geboes K,et al.The effect of preoperative radiation therapy on glucose utilization and cell kinetics in patients with primary rectal carcinoma[J].Cancer.1999,85(4):803-811.
4.Oya N,Nagata Y,Tamaki N,et al.FDG-PET evaluation of therapeutic effects on VX2 liver tumor[J].J Nucl Med.1996,37(2):296-302.
5.Riemann B,Konemann S,Popping D,et al.Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells[J].Strahlenther Onkol.2004,180(7):434-441.
6.Castellucci Paolo,Zinzani PierLuigi,Nanni Cristina,et al.18F-FDG PET early after radiotherapy lymphoma patients[J].Cancer Biotherapy & Radiopharmaceuticals.2004,19(5):606-612.
7.Wilson IK,Chatterjee S,Wolf W.Synthesis of 3'-fluoro-3'-deoxythymidine and studies of its ~(18)F-radiolabeling,as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS [J].J fluorine Chem.1991,55:283-289.
8.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with [F-18]FLT and positron emission tomography [J].Nat Med.1998,4:1334-1336.
9.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
10.Toyohara J,Waki A,Takamatsu S,et al.Basis of FLT as a cell proliferation marker:comparative uptake studies with[3H]thymidine and[3H]arabinothymidine,and cell-analysis in 22 asynchronously growing tumor cell lines[J].Nucl Med Biol.2002,29:281-287.
11.Eriksson S,Munch-Petersen B,Johansson K,et al.Structure and function of cellular deoxyribonucleoside kinases[J].Cell Mol Life Sci.2002,59:1327-1346.
12.Sugiyama M,Sakahara H,Sato K,et al.Evaluation of 3'-deoxy-3'-~(18)F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
13.Waldherr C,Mellinghoff IK,Tran C,et al.Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET[J].J Nucl Med.2005,46:114-120.
14.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-334.
15.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxythymidine (FLT)[J].Mol Imaging Biol.2007,9(6):340-347.
16.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy inandrogendependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
17.Chao KS.3'-deoxy-3'-(18)F-fluorothymidine(FLT) positron emission tomography for early prediction of response to chemoradiotherapy—a clinical application model of esophageal cancer[J].Semin Oncol.2007,34(2 Suppl 1):S31-36.
18.Sugiyama M,Sakahara H,Sato K,et al.Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
19.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors [J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
20.Kornberg A,Baker TA.Biosynthesis in DNA precursors [J].DNAreplication.2nd ed.New York:W.H.Freeman;1992,53-100.
21.Khanna KK,Jackson SP.DNA double-strand breaks:signaling,repair and the cancer connection.Nat Genet[J],2001,27:247-254.
22.He Q,Skog S,Welander I,et al.X-irradiation effects on thymidine kinase (TK):I.TK1 and 2 in normal and malignant cells[J].Cell Prolif.2002,35:69-81.
23.Fresno Vara JA,Casado E,de Castro J,et al.P13K/Akt signalling pathway and cancer[J].Cancer Treat Rev.2004,30:193-204.
24.Stanley JA,Shipley WU,Steel GG.Influece of tumor size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumor[J].Br J Cancer.1977,36(1):105-113.
25.Burgman P,Odonoghue JA,Humm JL,et al.Hypoxiainducedincrease in FDG uptake in MCF7 cells[J].J Nucl Med.2001,42:170-175.
26.Schelling M,Avril N,Naring J,et al.Positronemission tomography using (18F)fluorodeoxyglucose formonitoring primary chemotherapy in breast cancer[J].J Clin Oncol.2000,18:1689-1695.
1.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with [F-18]FLT and positron emission tomography.Nat Med[J].1998,4:1334-1336.
2.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
3.WHO handbook for reporting results of cancer treatment[M].Offset Publication No.48.Geneva (Switzerland).World Health Organization,1979.
4.Therasse P,Arbuck SG,Eisenhauer EA,et al.New guidelines to evaluate the response to treatment in solid tumors[J].J Natl Cancer Inst,2000,92(3):205-216.
5.Young H,Baum R,Cremerius U,et al:Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomo-graphy:review and 1999 EORTC recommendations.European Organization for Research and Treatment of Cancer (EORTC) PET Study Group[J].Eur J Cancer.1999,35:1773-1782.
6.Demetri GD,von Mehren M,Blanke CD,et al:Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours[J].N Engl J Med.2002,347:472-480.
7.Reske SN,Kotzerke J.FDG-PET for clinical use.Results of the 3rd German Interdisciplinary Consensus Conference,“Onko-PET Ⅲ”,21 July and 19 September 2000[J].Eur J Nucl Med.2001,28:1707-1723.
8.Gambhir SS.Molecular imaging of cancer with positron emission tomography [J].Nat Rev Cancer.2002,2:683-693.
9.Phelps ME.Positron emission tomography provides molecular imaging of biological processes[J].Proc Natl Acad Sci USA.2000,97:9226-9233.
10.Jerusalem G,Beguin Y,Fassotte MF,et al.Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease[J].Ann Oncol.2003,14:123-130.
11.Weber WA,Ott K.Imaging of esophageal and gastric cancer[J].Semin Oncol.2004,31:530-541.
12.Juweid ME,Cheson BD.Positron-emission tomography and assessment of cancer therapy [J].N Engl J Med.2006,354:496-507.
13.Delbeke D,Martin WH.PET and PET/CT for evaluation of colorectal carcinoma[J].Semin Nucl.2004,34(3):209-223.
14.Herzog D,Scher B,Helmbeger T,et al.PET/CT interventoional tumor therapy[J].Radiology.2004,44(11):1088—1095.
15.Huber KF,Buonocore E,Singh SK,et al.Characterization of chest masses by FDG positron emission tomography [J].J Nucl Med.1995,20:293-298.
16.Schirrmeister H,Kuhn T,Guhlmann A,et al.Fluorine-18-2-deoxy-2-fluoro-D-glucose PET in preoperative staging of breast cancer:comparison with the standard imaging procedures[J].J Nucl Med.2001,28:351-358.
17.Cook GJR,Fogelman I,Maisey MN.Normal physiological and benign pathological variants of 18-fluoro-2-deoxyglucose positron emission tomography scanning:potential for error in interpretation [J].Semin Nucl Med.1996,26:308-314.
18.Bakheet SM,Powe J.Benign causes of F-FDG uptake on whole body imaging[J].Semin Nucl Med.1998,28:352-358.
19.Mier W,Haberkom U,Eisenhut M.F-FLT:portrait of a proliferation marker[J].Eur J Nucl Med Mol Imaging.2002,29:165-169.
20.Shields AF.PET imaging with F-FLT and thymidine analogs:promise and pitfalls[J].J Nucl Med.2003,44:1432-1434.
21.Munch-Petersen B,Cloos L,Jensen HK,et al.Human thymidine kinase 1.Regulation in normal and malignant cells[J].Adv Enzyme Regul.1995,35:69-89.
22.Barthel H,Cleij MC,Collingridge DR,et al.3'-deoxy-3'-[~(18)F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography [J].Cancer Res.2003,63:3791-3798.
23.Wagner M,Seitz U,Buck A,et al.3'-[~(18)F]fluoro-3'-deoxythymidine ([～(18)F]-FLT) as positron emission tomography in a murine B-cell lymphoma model and in the human disease[J].Cancer Res.2003,63:2681-2687.
24.SugiyamaM,SakaharaH,SatoK,et al.Evaluation of 3'-deoxy-3'-18F-fluoro-thymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
25.Strauss LG,Conti PS.The applications of PET in clinical oncology.J Nucl Med[J].1991,32:623-648.
26.Bury T,Corhay JL,Duysinx B,et al.Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer[J].Eur RespirJ.1999,14:1376-1380.
27.Murayama C,Harada N,Kakiuchi T,et al.Evaluation of D-18F-FMT,18F-FDG,L-11C-MET,and 18F-FLT for monitoring the response of tumors to radiotherapy in mice[J].J Nucl Med.2009,50(2):290-5.
28.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy-thymidine (FLT) [J].Mol Imaging Biol.2007,9(6):340-347.
29.Riemann B,Konemann S,Popping D,et al.Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells[J].Strahlenther Onkol.2004,180(7):434-41.
30.Bonab AA,Weise SW,Syed SZ,et al.Monitoring treatment with a CDK2 inhibitor by microPET with 18F-FLT in a nude mouse tumor model.In:SNM 50th Annual Meeting 2003.
31.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
32.Van de Wiele C,Lahorte C,Oyen W,et al.Nuclear medicine imaging to predict response to radiotherapy:a review[J].Int J Radiat Oncol Biol Phys. 2003,55(1):5-15.
33.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-34.
34.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors[J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
35.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fiuoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy-thymidine(FLT)[J].Mol Imaging Biol.2007,9(6):340-7.
36.Tseng JR,Dandekar M,Subbarayan M,et al.Reproducibility of 3'-deoxy-3'-(18)F-fluorothymidine microPET studies in tumor xenografts in mice[J].J Nucl Med.2005,46(11):1851-1857.
37.Dandekar M,Tseng JR,Gambhirl SS,et al.Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts [J].J Nucl Med.2007,48(4):602-607.
1.殷蔚伯,余子豪,徐国镇等.肿瘤放射治疗学(第四版).北京:中国协和医科大学出版社,2007.578-612.
2.Hanahan D,Weinberg RA.The hallmarks of cancer[J].Cell.2000,100:57-70.
3.Crawford EJ,Christman D,Atkins H,et al.Scintigraphy with positronemitting compounds.-Carbon-11 labeled thymidine and thymidylate[J].Int J Nucl Med Biol.1978,5:61-69.
4.Martiat P,Ferrant A,Labar D,et al.In vivo measurement of carbon-11thymidine uptake in non-Hodgkin' s lymphoma using positron emission tomography[J].J Nucl Med.1988,29:1633-1637.
5.Eary JF,Mankoff DA,Spence AM,et al.2-[C-11]thymidine imaging of malignant brain tumors[J].Cancer Res.1999,59:615-621.
6.Wells P,Gunn RN,Alison M,et al.Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intraabdominal malignancies[J].Cancer Res.2002,62:5689-5702.
7.Conti PS,Alauddin MM,Fissekis JR,et al.Synthesis of 2'-fluoro-5-[~((11)C]-methyl-1-beta_D_arabinofuranosyluracil([~((11)C]-FMAU):a potential nucleoside analog for in vivo study of cellular proliferation with PET[J].Nucl Med Biol.1995,22:783-789.
8.Wilson IK,Chatterjee S,Wolf W.Synthesis of 3'-fluoro-3'-deoxythymidine and studies of its ~(18)F-radiolabeling,as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS[J].J fluorine Chem.1991,55:283-289.
9.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with[F-18]FLT and positron emission tomography[J].Nat Med 1998,4:1334-1336.
10.王荣福,刘红洁,张春丽.PET受体显像的研究应用进展[J].中国医学影 像技术．2006,22(10)：1599-1603．
11.Hicks RJ,Lau E,Alam NZ,et al.Imaging in the diagnosis and treatment of non-small cell lung cancer[J].Respirology.2007,12(2):165-172.
12.Blodgett TM,Meltzer CC,Townsend DW.PET/CT:form and function.Radiology[J].2007,242(2):360-385.
13.Israel O,Kuten A.Early detection of cancer recurrence:~(18)F-FDG PET/CT can make a difference in diagnosis and Patient care[J].J Nucl Med.2007,48 SuPPll:285-355.
14.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
15.Toyohara J,Waki A,Takamatsu S,et al.Basis of FLT as a cell proliferation marker:comparative uptake studies with [3H]thymidine and [3H]arabino-thymidine,and cell-analysis in 22 asynchronously growing tumor cell lines[J].Nucl Med Biol.2002,29:281-287.
16.Eriksson S,Munch-Petersen B,Johansson K,et al.Structure and function of cellular deoxyribonucleoside kinases[J].Cell Mol Life Sci.2002,59:1327-1346.
17.Vesselle H,Grierson J,Muzi M,et al.In vivo validation of 3-deoxy-3-[～(18)F]fluorothymidine ([～(18)F]FLT) as a proliferation imaging tracer in humans correlation of [F]FLT uptake by positron emission tumography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors [J].Clin Cancer Res.2002,8(11):3315-3323.
18.Yap CS,Czernin J,Fishbein MC,et al.Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-Positron emission Tomography[J].Chest.2006,129(2):393-401
19.Coles JP,Fryer TD,Bradley PG.et al.Intersubject variability and reproducibility of 150 PET studies[J].J Cereb Blood Flow Metab.2006,26(1):48-57.
20.Seitz U,Wagner M,Neumaier B,et al.Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3'-[~(18)F]fluoro-3'-deoxythymidine([~(18)F]FLT)in pancreatic cancer cell lines[J].Eur J Nucl Med Mol Imaging.2002,29:1174-1181.
21.Carter EA,McKuster K,Syed SZ,et al.Comparison of ~(18)FLT with ~(18)FDG for differentiation between tumor and focal sites of infection in rats[J].J Nucl Med.2002,43:266-270.
22.Van Waarde A,Cobben DCP,Suurmeijer AJH,et al.Selectivity of 3'-deoxy-3'-[~(18)F]fluorothymidine(FLT) and 2-[~(18)F]fluoro-2-deoxy-Dglucose (FDG) for tumor versus inflammation in a rodent model[J].J Nucl Med.2004,45:695-700.
23.Grierson JR,Shields AF.Radiosynthesis of 3'-deoxy-3'-[~(18)F]fluorothymidine:[~(18)F]FLT for imaging of cellular proliferation in vivo[J].Nucl Med Biol.2000,27:143-156.
24.Yun M,Oh SJ,Ha HJ,et al.High radiochemical yield synthesis of 3'-deoxy-3'-[~(18)F]fluorothymidine using(5'-O-dimethoxytrityl-2'-deoxy-3'-O-nosyl-beta-D-threo pentofuranosyl) thymine and its 3-N-BOC-protected analogue as a labeling precursor[J].Nucl Med Biol.2003,30:151-157.
25.Machulla HJ,Blochter A,Kuntzsch M,et al.Simplified labeling approach for synthesizing 3'-deoxy-3'-[~(18)F]fluorothymidine([~(18)F]FLT)[J].J Radioanal Nucl Chem.2000,243:843-846.
26.Delbeke D,Martin WH.PET and PET/CT for evaluation of colorectal carcinoma[J].Semin Nucl.2004,34(3):209-223.
27.Herzog D,Scher B,Helmbeger T,et al.PET/CT interventoional tumor therapy[J].Radiology.2004,44(11):1088-1095.
28.Dittmann H,Dohmen BM,Paulsen F,et al.[~(18)F]FLT PET for diagnosis and staging of thoracic tumours[J].Eur J Nucl Med Mol Imaging.2003,30(10):1407-1412.
29.Buck AK,Schirrmeister H,Hetzel M,et al.3-deoxy-3-[18F]fluorothymidine positron emission tomography for noninvasive assessment of proliferationin pulmonary nodules[J].Cancer Res.2002,62(9):3331-3334.
30.Buck AK,Halter G,Schirrmeister H,et al.Imaging proliferation in lung tumors with PET:18F-FLT versus 18F-FDG[J].J Nucl Med.2003,44(6):1426-1431.
31.田嘉禾,杨小丰、陈萍等.肺结节~(18)F-FLT和~(18)F-FDG PET/CT鉴别诊断的多中心临床研究[J].中国医学影像学杂志.2008,16(4):241-245.
32.WHO handbook for reporting results of cancer treatment[M].Offset Publication No.48.Geneva(Switzerland).World Health Organization,1979.
33.Therasse P,Arbuck SG,Eisenhauer EA,et al.New guidelines to evaluate the response to treatment in solid tumors[J].J Natl Cancer Inst,2000,92(3):205-216.
34.Young H,Baum R,Cremerius U,et al:Measurement of clinical and subclinical tumour response using[18F]-fluorodeoxyglucose and positron emission tomo-graphy:review and 1999 EORTC recommendations.European Organization for Research and Treatment of Cancer(EORTC) PET Study Group[J].Eur J Cancer.1999,35:1773-1782.
35.Demetri GD,von Mehren M,Blanke CD,et al:Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours[J].N Engl J Med.2002,347:472-480.
36.Reske SN,Kotzerke J.FDG-PET for clinical use.Results of the 3rd German Interdisciplinary Consensus Conference,"Onko-PET Ⅲ",21 July and 19September 2000[J].Eur J Nucl Med.2001,28:1707-1723.
37.Gambhir SS.Molecular imaging of cancer with positron emission tomography[J].Nat Rev Cancer.2002,2:683-693.
38.Phelps ME.Positron emission tomography provides molecular imaging of biological processes[J].Proc Natl Acad Sci U S A.2000,97:9226-9233.
39.Jerusalem G,Beguin Y,Fassotte MF,et al.Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease[J].Ann Oncol.2003,14:123-130.
40.Weber WA,Ott K.Imaging of esophageal and gastric cancer[J].Semin Oncol.2004,31:530-541.
41.Juweid ME,Cheson BD.Positron-emission tomography and assessment of cancer therapy[J].N Engl J Med.2006,354:496-507.
42.Barthel H,Cleij MC,Collingridge DR,et al.3'-deoxy-3'-[～(18)F]fluoro-thymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography [J].Cancer Res.2003,63:3791-3798.
43.Bonab AA,Weise SW,Syed SZ,et al.Monitoring treatment with a CDK2 inhibitor by microPET with 18F-FLT in a nude mouse tumor model.In:SNM 50th Annual Meeting 2003.
44.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
45.Van de Wiele C,Lahorte C,Oyen W,et al.Nuclear medicine imaging to predict response to radiotherapy:a review[J].Int J Radiat Oncol Biol Phys.2003,55(1):5-15.
46.SugiyamaM,SakaharaH,SatoK,et al.Evaluation of 3'-deoxy-3'-18F-fluoro-thymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
47.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-34.
48.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors[J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
49.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy- thymidine(FLT)[J].Mol Imaging Biol.2007,9(6):340-7.
50.Murayama C,Harada N,Kakiuchi T,et al.Evaluation of D-18F-FMT,18F-FDG,L-11C-MET,and 18F-FLT for monitoring the response of tumors to radiotherapy in mice[J].J Nucl Med.2009,50(2):290-5.
51.Lu L,Samuelsson L,Bergstrom M,et al.Rat studies comparing ~(11)C-FMAU,~(18)F-FLT,and ~(76)Br-BrFU as proliferation markers[J].J Nucl Med.2002,43(12):1688-1698.
2.Chien CR,Chen SW,Hsieh CY,et al.Intra-thoracic failure pattern and survival status following 3D conformal radiotherapy for non-small cell lung cancer:a preliminary report[J].Jpn J Clin Oncol,2001,31(2):55-60.
3.Schiepers C,Haustermans K,Geboes K,et al.The effect of preoperative radiation therapy on glucose utilization and cell kinetics in patients with primary rectal carcinoma[J].Cancer.1999,85(4):803-811.
4.Oya N,Nagata Y,Tamaki N,et al.FDG-PET evaluation of therapeutic effects on VX2 liver tumor[J].J Nucl Med.1996,37(2):296-302.
5.Riemann B,Konemann S,Popping D,et al.Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells[J].Strahlenther Onkol.2004,180(7):434-441.
6.Castellucci Paolo,Zinzani PierLuigi,Nanni Cristina,et al.18F-FDG PET early after radiotherapy lymphoma patients[J].Cancer Biotherapy & Radiopharmaceuticals.2004,19(5):606-612.
7.Wilson IK,Chatterjee S,Wolf W.Synthesis of 3'-fluoro-3'-deoxythymidine and studies of its ~(18)F-radiolabeling,as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS [J].J fluorine Chem.1991,55:283-289.
8.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with [F-18]FLT and positron emission tomography [J].Nat Med.1998,4:1334-1336.
9.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
10.Toyohara J,Waki A,Takamatsu S,et al.Basis of FLT as a cell proliferation marker:comparative uptake studies with[3H]thymidine and[3H]arabinothymidine,and cell-analysis in 22 asynchronously growing tumor cell lines[J].Nucl Med Biol.2002,29:281-287.
11.Eriksson S,Munch-Petersen B,Johansson K,et al.Structure and function of cellular deoxyribonucleoside kinases[J].Cell Mol Life Sci.2002,59:1327-1346.
12.Sugiyama M,Sakahara H,Sato K,et al.Evaluation of 3'-deoxy-3'-~(18)F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
13.Waldherr C,Mellinghoff IK,Tran C,et al.Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET[J].J Nucl Med.2005,46:114-120.
14.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-334.
15.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxythymidine (FLT)[J].Mol Imaging Biol.2007,9(6):340-347.
16.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy inandrogendependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
17.Chao KS.3'-deoxy-3'-(18)F-fluorothymidine(FLT) positron emission tomography for early prediction of response to chemoradiotherapy—a clinical application model of esophageal cancer[J].Semin Oncol.2007,34(2 Suppl 1):S31-36.
18.Sugiyama M,Sakahara H,Sato K,et al.Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
19.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors [J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
20.Kornberg A,Baker TA.Biosynthesis in DNA precursors [J].DNAreplication.2nd ed.New York:W.H.Freeman;1992,53-100.
21.Khanna KK,Jackson SP.DNA double-strand breaks:signaling,repair and the cancer connection.Nat Genet[J],2001,27:247-254.
22.He Q,Skog S,Welander I,et al.X-irradiation effects on thymidine kinase (TK):I.TK1 and 2 in normal and malignant cells[J].Cell Prolif.2002,35:69-81.
23.Fresno Vara JA,Casado E,de Castro J,et al.P13K/Akt signalling pathway and cancer[J].Cancer Treat Rev.2004,30:193-204.
24.Stanley JA,Shipley WU,Steel GG.Influece of tumor size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumor[J].Br J Cancer.1977,36(1):105-113.
25.Burgman P,Odonoghue JA,Humm JL,et al.Hypoxiainducedincrease in FDG uptake in MCF7 cells[J].J Nucl Med.2001,42:170-175.
26.Schelling M,Avril N,Naring J,et al.Positronemission tomography using (18F)fluorodeoxyglucose formonitoring primary chemotherapy in breast cancer[J].J Clin Oncol.2000,18:1689-1695.
1.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with [F-18]FLT and positron emission tomography.Nat Med[J].1998,4:1334-1336.
2.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
3.WHO handbook for reporting results of cancer treatment[M].Offset Publication No.48.Geneva (Switzerland).World Health Organization,1979.
4.Therasse P,Arbuck SG,Eisenhauer EA,et al.New guidelines to evaluate the response to treatment in solid tumors[J].J Natl Cancer Inst,2000,92(3):205-216.
5.Young H,Baum R,Cremerius U,et al:Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomo-graphy:review and 1999 EORTC recommendations.European Organization for Research and Treatment of Cancer (EORTC) PET Study Group[J].Eur J Cancer.1999,35:1773-1782.
6.Demetri GD,von Mehren M,Blanke CD,et al:Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours[J].N Engl J Med.2002,347:472-480.
7.Reske SN,Kotzerke J.FDG-PET for clinical use.Results of the 3rd German Interdisciplinary Consensus Conference,“Onko-PET Ⅲ”,21 July and 19 September 2000[J].Eur J Nucl Med.2001,28:1707-1723.
8.Gambhir SS.Molecular imaging of cancer with positron emission tomography [J].Nat Rev Cancer.2002,2:683-693.
9.Phelps ME.Positron emission tomography provides molecular imaging of biological processes[J].Proc Natl Acad Sci USA.2000,97:9226-9233.
10.Jerusalem G,Beguin Y,Fassotte MF,et al.Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease[J].Ann Oncol.2003,14:123-130.
11.Weber WA,Ott K.Imaging of esophageal and gastric cancer[J].Semin Oncol.2004,31:530-541.
12.Juweid ME,Cheson BD.Positron-emission tomography and assessment of cancer therapy [J].N Engl J Med.2006,354:496-507.
13.Delbeke D,Martin WH.PET and PET/CT for evaluation of colorectal carcinoma[J].Semin Nucl.2004,34(3):209-223.
14.Herzog D,Scher B,Helmbeger T,et al.PET/CT interventoional tumor therapy[J].Radiology.2004,44(11):1088—1095.
15.Huber KF,Buonocore E,Singh SK,et al.Characterization of chest masses by FDG positron emission tomography [J].J Nucl Med.1995,20:293-298.
16.Schirrmeister H,Kuhn T,Guhlmann A,et al.Fluorine-18-2-deoxy-2-fluoro-D-glucose PET in preoperative staging of breast cancer:comparison with the standard imaging procedures[J].J Nucl Med.2001,28:351-358.
17.Cook GJR,Fogelman I,Maisey MN.Normal physiological and benign pathological variants of 18-fluoro-2-deoxyglucose positron emission tomography scanning:potential for error in interpretation [J].Semin Nucl Med.1996,26:308-314.
18.Bakheet SM,Powe J.Benign causes of F-FDG uptake on whole body imaging[J].Semin Nucl Med.1998,28:352-358.
19.Mier W,Haberkom U,Eisenhut M.F-FLT:portrait of a proliferation marker[J].Eur J Nucl Med Mol Imaging.2002,29:165-169.
20.Shields AF.PET imaging with F-FLT and thymidine analogs:promise and pitfalls[J].J Nucl Med.2003,44:1432-1434.
21.Munch-Petersen B,Cloos L,Jensen HK,et al.Human thymidine kinase 1.Regulation in normal and malignant cells[J].Adv Enzyme Regul.1995,35:69-89.
22.Barthel H,Cleij MC,Collingridge DR,et al.3'-deoxy-3'-[~(18)F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography [J].Cancer Res.2003,63:3791-3798.
23.Wagner M,Seitz U,Buck A,et al.3'-[~(18)F]fluoro-3'-deoxythymidine ([～(18)F]-FLT) as positron emission tomography in a murine B-cell lymphoma model and in the human disease[J].Cancer Res.2003,63:2681-2687.
24.SugiyamaM,SakaharaH,SatoK,et al.Evaluation of 3'-deoxy-3'-18F-fluoro-thymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
25.Strauss LG,Conti PS.The applications of PET in clinical oncology.J Nucl Med[J].1991,32:623-648.
26.Bury T,Corhay JL,Duysinx B,et al.Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer[J].Eur RespirJ.1999,14:1376-1380.
27.Murayama C,Harada N,Kakiuchi T,et al.Evaluation of D-18F-FMT,18F-FDG,L-11C-MET,and 18F-FLT for monitoring the response of tumors to radiotherapy in mice[J].J Nucl Med.2009,50(2):290-5.
28.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy-thymidine (FLT) [J].Mol Imaging Biol.2007,9(6):340-347.
29.Riemann B,Konemann S,Popping D,et al.Early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in rat C6 glioma cells[J].Strahlenther Onkol.2004,180(7):434-41.
30.Bonab AA,Weise SW,Syed SZ,et al.Monitoring treatment with a CDK2 inhibitor by microPET with 18F-FLT in a nude mouse tumor model.In:SNM 50th Annual Meeting 2003.
31.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
32.Van de Wiele C,Lahorte C,Oyen W,et al.Nuclear medicine imaging to predict response to radiotherapy:a review[J].Int J Radiat Oncol Biol Phys. 2003,55(1):5-15.
33.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-34.
34.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors[J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
35.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fiuoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy-thymidine(FLT)[J].Mol Imaging Biol.2007,9(6):340-7.
36.Tseng JR,Dandekar M,Subbarayan M,et al.Reproducibility of 3'-deoxy-3'-(18)F-fluorothymidine microPET studies in tumor xenografts in mice[J].J Nucl Med.2005,46(11):1851-1857.
37.Dandekar M,Tseng JR,Gambhirl SS,et al.Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts [J].J Nucl Med.2007,48(4):602-607.
1.殷蔚伯,余子豪,徐国镇等.肿瘤放射治疗学(第四版).北京:中国协和医科大学出版社,2007.578-612.
2.Hanahan D,Weinberg RA.The hallmarks of cancer[J].Cell.2000,100:57-70.
3.Crawford EJ,Christman D,Atkins H,et al.Scintigraphy with positronemitting compounds.-Carbon-11 labeled thymidine and thymidylate[J].Int J Nucl Med Biol.1978,5:61-69.
4.Martiat P,Ferrant A,Labar D,et al.In vivo measurement of carbon-11thymidine uptake in non-Hodgkin' s lymphoma using positron emission tomography[J].J Nucl Med.1988,29:1633-1637.
5.Eary JF,Mankoff DA,Spence AM,et al.2-[C-11]thymidine imaging of malignant brain tumors[J].Cancer Res.1999,59:615-621.
6.Wells P,Gunn RN,Alison M,et al.Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intraabdominal malignancies[J].Cancer Res.2002,62:5689-5702.
7.Conti PS,Alauddin MM,Fissekis JR,et al.Synthesis of 2'-fluoro-5-[~((11)C]-methyl-1-beta_D_arabinofuranosyluracil([~((11)C]-FMAU):a potential nucleoside analog for in vivo study of cellular proliferation with PET[J].Nucl Med Biol.1995,22:783-789.
8.Wilson IK,Chatterjee S,Wolf W.Synthesis of 3'-fluoro-3'-deoxythymidine and studies of its ~(18)F-radiolabeling,as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS[J].J fluorine Chem.1991,55:283-289.
9.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation in vivo with[F-18]FLT and positron emission tomography[J].Nat Med 1998,4:1334-1336.
10.王荣福,刘红洁,张春丽.PET受体显像的研究应用进展[J].中国医学影 像技术．2006,22(10)：1599-1603．
11.Hicks RJ,Lau E,Alam NZ,et al.Imaging in the diagnosis and treatment of non-small cell lung cancer[J].Respirology.2007,12(2):165-172.
12.Blodgett TM,Meltzer CC,Townsend DW.PET/CT:form and function.Radiology[J].2007,242(2):360-385.
13.Israel O,Kuten A.Early detection of cancer recurrence:~(18)F-FDG PET/CT can make a difference in diagnosis and Patient care[J].J Nucl Med.2007,48 SuPPll:285-355.
14.Rasey JS,Grierson JR,Wiens LW,et al.Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells[J].J Nucl Med.2002,43:1210-1217.
15.Toyohara J,Waki A,Takamatsu S,et al.Basis of FLT as a cell proliferation marker:comparative uptake studies with [3H]thymidine and [3H]arabino-thymidine,and cell-analysis in 22 asynchronously growing tumor cell lines[J].Nucl Med Biol.2002,29:281-287.
16.Eriksson S,Munch-Petersen B,Johansson K,et al.Structure and function of cellular deoxyribonucleoside kinases[J].Cell Mol Life Sci.2002,59:1327-1346.
17.Vesselle H,Grierson J,Muzi M,et al.In vivo validation of 3-deoxy-3-[～(18)F]fluorothymidine ([～(18)F]FLT) as a proliferation imaging tracer in humans correlation of [F]FLT uptake by positron emission tumography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors [J].Clin Cancer Res.2002,8(11):3315-3323.
18.Yap CS,Czernin J,Fishbein MC,et al.Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-Positron emission Tomography[J].Chest.2006,129(2):393-401
19.Coles JP,Fryer TD,Bradley PG.et al.Intersubject variability and reproducibility of 150 PET studies[J].J Cereb Blood Flow Metab.2006,26(1):48-57.
20.Seitz U,Wagner M,Neumaier B,et al.Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3'-[~(18)F]fluoro-3'-deoxythymidine([~(18)F]FLT)in pancreatic cancer cell lines[J].Eur J Nucl Med Mol Imaging.2002,29:1174-1181.
21.Carter EA,McKuster K,Syed SZ,et al.Comparison of ~(18)FLT with ~(18)FDG for differentiation between tumor and focal sites of infection in rats[J].J Nucl Med.2002,43:266-270.
22.Van Waarde A,Cobben DCP,Suurmeijer AJH,et al.Selectivity of 3'-deoxy-3'-[~(18)F]fluorothymidine(FLT) and 2-[~(18)F]fluoro-2-deoxy-Dglucose (FDG) for tumor versus inflammation in a rodent model[J].J Nucl Med.2004,45:695-700.
23.Grierson JR,Shields AF.Radiosynthesis of 3'-deoxy-3'-[~(18)F]fluorothymidine:[~(18)F]FLT for imaging of cellular proliferation in vivo[J].Nucl Med Biol.2000,27:143-156.
24.Yun M,Oh SJ,Ha HJ,et al.High radiochemical yield synthesis of 3'-deoxy-3'-[~(18)F]fluorothymidine using(5'-O-dimethoxytrityl-2'-deoxy-3'-O-nosyl-beta-D-threo pentofuranosyl) thymine and its 3-N-BOC-protected analogue as a labeling precursor[J].Nucl Med Biol.2003,30:151-157.
25.Machulla HJ,Blochter A,Kuntzsch M,et al.Simplified labeling approach for synthesizing 3'-deoxy-3'-[~(18)F]fluorothymidine([~(18)F]FLT)[J].J Radioanal Nucl Chem.2000,243:843-846.
26.Delbeke D,Martin WH.PET and PET/CT for evaluation of colorectal carcinoma[J].Semin Nucl.2004,34(3):209-223.
27.Herzog D,Scher B,Helmbeger T,et al.PET/CT interventoional tumor therapy[J].Radiology.2004,44(11):1088-1095.
28.Dittmann H,Dohmen BM,Paulsen F,et al.[~(18)F]FLT PET for diagnosis and staging of thoracic tumours[J].Eur J Nucl Med Mol Imaging.2003,30(10):1407-1412.
29.Buck AK,Schirrmeister H,Hetzel M,et al.3-deoxy-3-[18F]fluorothymidine positron emission tomography for noninvasive assessment of proliferationin pulmonary nodules[J].Cancer Res.2002,62(9):3331-3334.
30.Buck AK,Halter G,Schirrmeister H,et al.Imaging proliferation in lung tumors with PET:18F-FLT versus 18F-FDG[J].J Nucl Med.2003,44(6):1426-1431.
31.田嘉禾,杨小丰、陈萍等.肺结节~(18)F-FLT和~(18)F-FDG PET/CT鉴别诊断的多中心临床研究[J].中国医学影像学杂志.2008,16(4):241-245.
32.WHO handbook for reporting results of cancer treatment[M].Offset Publication No.48.Geneva(Switzerland).World Health Organization,1979.
33.Therasse P,Arbuck SG,Eisenhauer EA,et al.New guidelines to evaluate the response to treatment in solid tumors[J].J Natl Cancer Inst,2000,92(3):205-216.
34.Young H,Baum R,Cremerius U,et al:Measurement of clinical and subclinical tumour response using[18F]-fluorodeoxyglucose and positron emission tomo-graphy:review and 1999 EORTC recommendations.European Organization for Research and Treatment of Cancer(EORTC) PET Study Group[J].Eur J Cancer.1999,35:1773-1782.
35.Demetri GD,von Mehren M,Blanke CD,et al:Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours[J].N Engl J Med.2002,347:472-480.
36.Reske SN,Kotzerke J.FDG-PET for clinical use.Results of the 3rd German Interdisciplinary Consensus Conference,"Onko-PET Ⅲ",21 July and 19September 2000[J].Eur J Nucl Med.2001,28:1707-1723.
37.Gambhir SS.Molecular imaging of cancer with positron emission tomography[J].Nat Rev Cancer.2002,2:683-693.
38.Phelps ME.Positron emission tomography provides molecular imaging of biological processes[J].Proc Natl Acad Sci U S A.2000,97:9226-9233.
39.Jerusalem G,Beguin Y,Fassotte MF,et al.Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease[J].Ann Oncol.2003,14:123-130.
40.Weber WA,Ott K.Imaging of esophageal and gastric cancer[J].Semin Oncol.2004,31:530-541.
41.Juweid ME,Cheson BD.Positron-emission tomography and assessment of cancer therapy[J].N Engl J Med.2006,354:496-507.
42.Barthel H,Cleij MC,Collingridge DR,et al.3'-deoxy-3'-[～(18)F]fluoro-thymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography [J].Cancer Res.2003,63:3791-3798.
43.Bonab AA,Weise SW,Syed SZ,et al.Monitoring treatment with a CDK2 inhibitor by microPET with 18F-FLT in a nude mouse tumor model.In:SNM 50th Annual Meeting 2003.
44.Oyama N,Ponde DE,Dence C,et al.Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation[J].J Nucl Med.2004,45:519-525.
45.Van de Wiele C,Lahorte C,Oyen W,et al.Nuclear medicine imaging to predict response to radiotherapy:a review[J].Int J Radiat Oncol Biol Phys.2003,55(1):5-15.
46.SugiyamaM,SakaharaH,SatoK,et al.Evaluation of 3'-deoxy-3'-18F-fluoro-thymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice[J].J Nucl Med.2004,45:1754-1758.
47.Pan MH,Huang SC,Liao YP,et al.FLT-PET imaging of radiation responses in murine tumors[J].Mol Imaging Biol.2008,10(6):325-34.
48.Yang YJ,Ryu JS,Kim SY,et al.Use of 3'-deoxy-3'-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors[J].Eur J Nucl Med Mol Imaging.2006,33(4):412-419.
49.Molthoff CF,Klabbers BM,Berkhof J,et al.Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice:comparison of 2'-deoxy-2'-[18F]fluoro-D-glucose(FDG) and 3'-[18F]fluoro-3'-deoxy- thymidine(FLT)[J].Mol Imaging Biol.2007,9(6):340-7.
50.Murayama C,Harada N,Kakiuchi T,et al.Evaluation of D-18F-FMT,18F-FDG,L-11C-MET,and 18F-FLT for monitoring the response of tumors to radiotherapy in mice[J].J Nucl Med.2009,50(2):290-5.
51.Lu L,Samuelsson L,Bergstrom M,et al.Rat studies comparing ~(11)C-FMAU,~(18)F-FLT,and ~(76)Br-BrFU as proliferation markers[J].J Nucl Med.2002,43(12):1688-1698.