Graf Nicolas, Herrmann Ken, den Hollander Jürgen, Fend Falko, Schuster Tibor, Wester Hans-Jürgen, Senekowitsch-Schmidtke Reingard, zum Büschenfelde Christian Meyer, Peschel Christian, Schwaiger Markus, Dechow Tobias, Buck Andreas K
Department of Hematology and Oncology, Technische Universität München, Ismaninger Strasse 22, 81675, Munich, Germany.
Mol Imaging Biol. 2008 Nov-Dec;10(6):349-55. doi: 10.1007/s11307-008-0162-3. Epub 2008 Aug 14.
Positron emission tomography with the thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been reported to closely reflect lymphoma proliferation in vivo. In this preclinical study, we have investigated if FLT can also be utilized for imaging therapy-induced alterations of the nucleoside metabolism and if FLT is a surrogate marker for early response to cytotoxic treatment.
Immunodeficient mice bearing high-grade lymphoma xenotransplants were treated with the cytotoxic agent doxorubicin (day 0). In the time course of day +1 to +9, antiproliferative effects were assessed non-invasively with FLT-PET and correlated to changes of the proliferation fraction and induction of apoptosis, as assessed by immunohistochemistry.
Tumor growth in untreated animals was significantly higher than in treated animals. In FLT-PET scans, these observations correlated with a significant decrease of tumor-to-background ratio in the therapy group already at day 1. Likewise, median tumor-to-muscle ratio of FLT uptake already declined at day 1. The proliferation fraction assessed by Ki-67 immunohistochemistry decreased after chemotherapy, while activated caspase 3 increased, suggesting both cell cycle arrest and induction of apoptosis as underlying mechanisms of the observed PET-signal alterations.
In a lymphoma xenotransplant model, we show that positron emission tomography using the proliferation marker FLT is suitable to detect early response to cytotoxic treatment. A significant decrease of FLT uptake but not tumor growth was detectable already 24 h after therapy and correlated with reduced proliferation and induction of apoptosis. Thus, FLT-PET has a potential for imaging early response to treatment in malignant lymphoma.
据报道，使用胸苷类似物3'-脱氧-3'-[18F]氟胸苷（FLT）的正电子发射断层扫描能够在体内密切反映淋巴瘤的增殖情况。在这项临床前研究中，我们调查了FLT是否也可用于成像治疗引起的核苷代谢变化，以及FLT是否是细胞毒性治疗早期反应的替代标志物。
用细胞毒性药物阿霉素（第0天）治疗携带高级别淋巴瘤异种移植的免疫缺陷小鼠。在第1天至第9天的时间过程中，用FLT-PET对抗增殖作用进行无创评估，并与通过免疫组织化学评估的增殖分数变化和细胞凋亡诱导情况相关联。
未治疗动物的肿瘤生长明显高于治疗动物。在FLT-PET扫描中，这些观察结果与治疗组在第1天肿瘤与背景比值的显著降低相关。同样，FLT摄取的肿瘤与肌肉比值中位数在第1天就已下降。化疗后，通过Ki-67免疫组织化学评估的增殖分数降低，而活化的半胱天冬酶3增加，这表明细胞周期停滞和细胞凋亡诱导都是观察到的PET信号改变的潜在机制。
在淋巴瘤异种移植模型中，我们表明使用增殖标志物FLT的正电子发射断层扫描适用于检测对细胞毒性治疗的早期反应。治疗后24小时即可检测到FLT摄取的显著降低而非肿瘤生长，且与增殖减少和细胞凋亡诱导相关。因此，FLT-PET在恶性淋巴瘤治疗早期反应成像方面具有潜力。
