IN VIVO MARKER OF CELL PROLIFERATION FOR PET STUDIES

形态学成像的进展，特别是MRI和CT， 显著改善肿瘤检测、分期和治疗测量 反应 通过成像改善癌症患者管理是 不太可能继续以类似的速度，除非解剖学研究， 增强了对肿瘤生物学和体内代谢的评估。 利用正电子发射断层扫描已经朝着这个目标取得了进展 (PET)和葡萄糖利用的体内放射性示踪剂，[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，最多是间接测量细胞 增殖 研究人员采用传统的方法， 测量DNA合成，如测定生物分布， 生物化学放射性测定和[3 H]或[14 C] TdR放射自显影，以及 作为免疫组化与溴脱氧尿苷（BUdR），以验证 [11 C] TdR与PET的使用。围绕着许多问题， 用[11 C]定量DNA合成的体内方法的开发 TdR，也许最麻烦的是它的快速体内催化剂， 使PET动力学数据的解释复杂化。 我们特别建议 解决这个问题，并假设细胞增殖的测量 相当于体积有丝分裂指数（MIv），即，肿瘤体积分数 分裂（S期细胞）所占据的体积可以在体内实现， 使用胸苷的非分解代谢核苷类似物的PET： 2 '-氟-5-[11 C]-甲基-1-β-D-阿拉伯呋喃糖基尿嘧啶（FMAU）。 的 将检验这种放射性示踪剂监测DNA合成的功效 在动物肿瘤模型和患者中，与MIv相比， 用BUdR和定量组织学。 使用[14 C] FMAU的研究证实了 血浆中不存在显著的标记催化剂，证明 肿瘤可以用PET很好地可视化，并且表明肿瘤中的摄取 正常器官与MIv呈正相关。 我们建议测试 假设细胞增殖的测量平行于BUdR 有丝分裂指数可以用PET和[11 C]FMAU在体内获得。

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.