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Development of Nuclear Medicine Technique for the Evaluation of Cell Proliferation Kinetics, Directry Contributing to Cancer Treatment

开发用于评估细胞增殖动力学的核医学技术，直接有助于癌症治疗

基本信息

批准号：
09470196
负责人：
FUKUDA Hiroshi
金额：
$ 6.14万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

We optimized a double labeling method using ^3H-thymidine and anti BrdUrd antibodies for measuring potential doubling time (Tpot) of animal tumors. Then, we measured growth kinetics of a mouse tumor after irradiation and found that Tpot values were inhomogeneous within a tumor during fractionated irradiation and that some population grew as rapid as un-irradiated tumors. We could demonstrate the accelerated re-population during irradiation . Such kind information is very important for radiotherapy planning. Tpot measurement in humans by nuclear medicine should be developed.As tracers for the evaluation of cell proliferation, iodine-labeled uridine derivatives and ^<11>C-thymidines were evaluated from the view point of stability and metabolism in the serum and tissues. These tracers proved not o be suitable for our purposes, because the former is de-iodinated in the blood and tissues and latter is metabolized in the tissues and thus estimation of DNA binding fraction will be very diffic … More ult. While ^<18>F-3'-deoxy-3'- fluorothymidine ([^<18>F]FLT) was reported to be stable in the blood and trapped in the proliferating tissues. We decided [^<18>F]FLT is the best tracer for visualizing proliferative activity of tumors in vivo. Then, we tested radiosynthesis of [^<18>F]FLT and evaluated its efficacy for clinical application.The radiosynthesis was performed according to the literature ; [^<18>F]Fluoride was reacted with the substrate dissolved in acetonitrile at 100℃ for 15 min. After deprotection by addition of cesium ammonium nitrate the crude product was purified by passing through a short column and finally by HPLC separation. The radiochemically pure [^<18>F]FLT was obtained in overall radiochemical yields of 6-8% within 100 min. We concluded that the method was reproducible despite our lower yields compared to the reported value of 13%. Biodistribution studies with rats showed that [^<18>F]FLT was remarkably accumulated in bone marrow as expected. We have already obtained data for exposure dose and acute toxicity from a preceding research group in USA and thus finished the preparation for clinical use of [^<18>F]FLT.However, it should be pointed out that our method based on manual operation must be automated for routine practice and that it requires another investment.We have also started to develop new ^<18>F-labeled tumor imaging agents, based on analogous design of microtubular and matrix metalloproteinase inhibitors which are closely related to tumor proliferation. Less

我们优化了一种使用~3H-胸腺嘧啶核苷和抗BrdUrd抗体的双重标记方法来测量动物肿瘤的潜在倍增时间(Tpot)。然后，我们测量了照射后小鼠肿瘤的生长动力学，发现在分次照射期间，肿瘤内的Tpot值是不均匀的，并且一些种群的生长速度与未照射的肿瘤一样快。我们可以证明在辐射过程中加速了再布居。这类信息对于放射治疗计划是非常重要的。作为评价细胞增殖的示踪剂，从血清和组织的稳定性和代谢角度对碘标记尿苷衍生物和C-胸腺嘧啶核苷进行了评价。这些示踪剂被证明不适合我们的目的，因为前者在血液和组织中去碘，而后者在组织中代谢，因此dna结合分数的估计将非常困难…。更糟的是。而^&lt；18&gt；F-3‘-脱氧-3’-氟代胸苷([^&lt；18&gt；18&gt；F]flt)则被报道在血液中稳定存在，并被捕获在增殖组织中。我们认为Flt是显示体内肿瘤增殖活性的最佳示踪剂。然后，我们测试了[^&lt；18&gt；F]flt的放射合成，并评价了其临床应用的效果。放射合成按照文献进行：[^&lt；18&gt；F]氟与底物在100℃的乙腈中反应15分钟。粗品经硝酸铯铵脱保护后，经短柱纯化，再经高效液相色谱分离。在100分钟内获得放化纯的放化产物，放化总产率为6-8%。我们的结论是，尽管与报道的13%的产量相比，该方法的得率较低，但该方法是可重复的。在大鼠体内的生物分布研究表明，[^&lt；18&gt；F]flt如预期的那样在骨髓中显著蓄积。我们已经从美国的前一个研究小组获得了暴露剂量和急性毒性的数据，从而完成了临床使用的准备工作。但需要指出的是，我们基于人工操作的方法必须自动化才能进行常规操作，需要另一项投资。我们还开始开发新的标记肿瘤显像剂，基于与肿瘤增殖密切相关的微管和基质金属蛋白酶抑制剂的类似设计。较少