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

我们使用 ^3H-胸苷和抗Brdurd抗体优化了一种双重标记方法，用于测量动物肿瘤的潜在双倍时间（TPOT）。然后，我们测量了辐照后小鼠肿瘤的生长动力学，发现在分离辐射过程中，TPOT值在肿瘤中不均匀，并且某些种群的生长与未辐照的肿瘤一样快。我们可以在辐射过程中证明加速的重建。这样的信息对于放射治疗计划非常重要。应通过核医学对人类进行TPOT测量。作为评估细胞增殖，碘标记的尿苷衍生物的示踪剂，并从血清和组织中的稳定性和代谢的角度评估了 ^<11> c-胸苷。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被固定在组织中，后来在组织中代谢，因此对DNA结合分数的估计将非常困难……更ult。据报道， ^<18> f-3'-脱氧-3'--氟噻氨者们（[ ^<18> f] flt）在血液中稳定，被困在增殖的组织中。我们认为[^<18> f] FLT是可视化体内肿瘤活性的最佳示踪剂。然后，我们测试了[^<18> f] FLT的放射性合成，并评估了其临床应用的有效性。根据文献进行了放射合成。 [^<18> f]氟化物与底物在100℃溶解在乙腈中15分钟。通过添加硝酸铵硝酸盐脱落后，通过短柱并通过HPLC分离来纯化粗产物。在100分钟内，放射化学上的纯净[^<18> f] FLT以6-8％的总体放射化学产率获得。我们得出的结论是，该方法是可复制的目的地，而较低的产量与报告的值为13％相比。与大鼠的生物分布研究表明，如预期的那样，[^<18> f] FLT在骨髓中显着积累。我们已经从美国先前的研究小组获得了暴露剂量和急性毒性的数据，因此完成了临床使用[ ^<18> f] flt的准备。与肿瘤增殖密切相关的基质金属蛋白酶抑制剂。较少的