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

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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