IN VIVO MARKER OF CELL PROLIFERATION FOR PET STUDIES

形态成像的进展，特别是MRI和CT，有 显著改进了肿瘤的检测、分期和治疗措施 回应。通过成像改善癌症患者管理 不太可能以类似的速度继续下去，除非解剖学研究 增加了对肿瘤生物学和体内新陈代谢的评估。 使用正电子发射断层摄影术已经朝着这个目标取得了进展。 和体内葡萄糖利用的放射性示踪剂，[18F] 氟脱氧葡萄糖(FDG)。然而，目前使用的FDG和其他放射性示踪剂 在PET肿瘤学研究中，充其量是细胞的间接测量 扩散。调查人员使用了传统的方法来 测量DNA合成，如确定生物分布， 生化放射分析和[~3H]或[~(14)C]TdR放射自显影 以溴脱氧尿嘧啶核苷(BUDR)免疫组织化学方法验证 [11C]TdR与PET的使用。在围绕着的许多问题中 [11C]体内DNA合成定量方法的建立 TDR，也许最麻烦的是它在体内的快速分解代谢，这 使PET动力学数据的解释复杂化。我们建议具体地 解决这个问题，并假设一种细胞增殖的测量 相当于体积分裂指数(MIV)，即肿瘤的比例 在体内可以实现细胞分裂(S期细胞)所占的体积 使用胸腺嘧啶核苷的非降解核苷类似物的PET： 2‘-fluoro-5-[11C]-methyl-1-beat-D-arabinofuranosyluracil(FMAU)。这个 这种放射性示踪剂用于监测dna合成的有效性将被检验。 在动物肿瘤模型和患者中与MIV进行比较 结合BUDR和定量组织学。使用[14C]FMAU的研究证实 血浆中没有显著标记的分解代谢物，说明 PET可以很好地显示肿瘤，并表明肿瘤的摄取 正常器官与MIV呈正相关。我们打算测试一下 细胞增殖测定平行于BUR的假设 用PET和[11C]FMAU可以在体内获得有丝分裂指数。

Advances in morphological imaging, particularly MRI and CT, have significantly improved tumor detection, staging and measurement of therapy response. Improvement in cancer patient management through imaging is unlikely to continue at a similar rate unless anatomical studies are augmented with an assessment of tumor biology and metabolism in vivo. Progress towards this goal has been made using positron emission tomography (PET) and an in vivo radiotracer of glucose utilization, [18F] fluodeoxyglucose (FDG). However, FDG and other radiotracers currently used in PET oncology studies are, at best, indirect measures of cell proliferation. Investigators have employed traditional methodologies for measuring DNA synthesis, such as determination of biodistribution, biochemical radioassay, and autoradiography with [3H] or [14C] TdR, as well as immunohistochemistry with bromodeoxyuridine (BUdR), in order to validate the use of [11C] TdR with PET. Among the many issues surrounding development of an in vivo method for quantitating DNA synthesis with [11C] TdR, perhaps the most cumbersome is its rapid in vivo catabolism, which complicates interpretation of PET kinetic data. We propose to specifically address this issue and hypothesize that a measurement of cell proliferation equivalent to volumetric mitotic index (MIv), i.e., the fraction of tumor volume occupied by dividing (S-phase cells) can be achieved in vivo with PET using a non-catabolized nucleoside anolog of thkymidine: 2'-fluoro-5-[11C]-methyl-1-beat-D-arabinofuranosyluracil (FMAU). The efficacy of this radiotracaer for monitoring DNA synthesis will be examined in animal tumor models and patients in comparison with MIv, as measured with BUdR and quantitative histology. Studies using [14C] FMAU confirm the absence of significant labeled catabolites in plasma, demonstrate that tumors can be well visualized with PET, and indicate that uptake into tumor and normal organs is positively correlated with MIv. We propose to test the hypothesis that measurements of cell proliferaton paralleling BUdR mitotic index can be obtained in vivo with PET and [11C]FMAU.