Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies.
Kinetic analysis of 2-[11C]thymidine PET imaging studies: validation studies.
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发表时间：
1999-04
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通讯作者：
D. Mankoff;Anthony F. Shields;J. Link;Michael M. Graham;M. Muzi;L. Peterson;J. Eary;K. Krohn
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作者：
D. Mankoff;Anthony F. Shields;J. Link;Michael M. Graham;M. Muzi;L. Peterson;J. Eary;K. Krohn
未标记的 2-[11C]胸苷已作为细胞增殖的 PET 示踪剂进行了测试。我们之前描述了胸苷和标记代谢物动力学模型，用于量化胸苷进入 DNA 的通量，作为肿瘤增殖的衡量标准。我们在此描述研究结果，以验证模型的一些假设并测试模型预测示踪剂掺入肿瘤 DNA 的时间过程的能力。方法进行了三组研究：（a）注射后早期测量正常小鼠增殖组织中示踪剂的摄取，以评估胸苷和胸苷分解代谢代谢物（胸腺嘧啶和CO2）的相对递送并计算相对血液组织转移率（相对K1s）。 （b）通过在正常人类志愿者中连续注射[11C]胸苷和[11C]胸腺嘧啶，测量第一个标记代谢物的动力学，以确定它是否被捕获在增殖组织（例如骨髓）中。 (c) 在多肿瘤大鼠模型中，进行 2-[14C]胸苷注射、肿瘤取样和定量 DNA 提取，以测量标记摄取到 DNA 中的时间过程，以便与模型预测进行比较。结果 对小鼠的研究表明，胸苷和代谢物在体细胞组织中的相对递送是一致的，但正如预期的那样，与 CO2 相比，胸苷和胸腺嘧啶在正常大脑中的递送减少。对志愿者进行的胸腺嘧啶研究表明，与胸腺嘧啶核苷相比，标记在骨髓中的捕获量极少。这种捕获量可以通过组织中少量标记的二氧化碳固定来解释，这一过程包含在模型中。大鼠摄取实验显示标记已早期掺入 DNA，并且该模型能够拟合摄取的时间过程。结论 这些初步研究支持区室模型的假设，并证明其能够使用 2-[11C]胸苷和 PET 定量进入 DNA 的胸苷通量。结果表明，有必要开展进一步的工作来研究肿瘤异质性的影响，并将肿瘤增殖的 PET 测量结果与体外增殖测量结果以及接受治疗的患者的临床肿瘤行为进行比较。
UNLABELLED 2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. METHODS Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. RESULTS Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. CONCLUSION These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.