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

我们优化了一种使用^3H-胸苷和抗BrdUrd抗体的双标记方法，用于测量动物肿瘤的潜在倍增时间（Tpot）。然后，我们测量了照射后的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，并且一些群体与未照射的肿瘤一样快速生长。我们可以证明辐射过程中加速的再增殖。这类信息对于放射治疗计划的制定是非常重要的。作为评价细胞增殖的示踪剂，<11>从血清和组织中的稳定性和代谢的观点评价了碘标记的尿苷衍生物和~ 1C-胸苷。这些示踪剂不适合我们的目的，因为前者在血液和组织中脱碘，后者在组织中代谢，因此DNA结合分数的估计将非常困难 ...更多信息 而据报道，13 <18>F-3 '-脱氧-3'-氟胸苷（[13 <18>F]FLT）在血液中是稳定的，并被捕获在增殖的组织中。我们决定<18>FLT是用于可视化体内肿瘤增殖活性的最佳示踪剂。根据<18>文献报道，[^F]FLT<18>与底物在乙腈中于100℃反应15 min，加入硝酸铯铵脱保护后，粗产物通过短柱纯化，最后通过HPLC分离。在100 min内获得放射化学纯的[^<18>F]FLT，总放射化学产率为6-8%。我们得出结论，尽管与报道的13%的值相比，我们的产率较低，但该方法具有重现性。大鼠的生物分布研究表明，[^<18>F]FLT如预期的那样在骨髓中显著蓄积。我们已经从美国的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[^ F]FLT的临床应用准备<18>，但需要指出的是，我们的方法是基于人工操作的，必须自动化才能进行常规实践，这需要额外的投资。我们还开始开发新的^<18>F标记的肿瘤显像剂，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。少

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