Center for Radiopharmaceutical Science, Eidgenoessische Technische Hochschule, Zurich, Switzerland.
Transl Oncol. 2010 Aug 1;3(4):264-75. doi: 10.1593/tlo.10127.
Noninvasive functional imaging of tumors can provide valuable early-response biomarkers, in particular, for targeted chemotherapy. Using various experimental tumor models, we have investigated the ability of positron emission tomography (PET) measurements of 2-deoxy-2-[(18)F]fluoro-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) to detect response to the allosteric mammalian target of rapamycin (mTOR) inhibitor everolimus. Tumor models were declared sensitive (murine melanoma B16/BL6 and human lung H596) or relatively insensitive (human colon HCT116 and cervical KB31), according to the IC(50) values (concentration inhibiting cell growth by 50%) for inhibition of proliferation in vitro (<10 nM and >1 microM, respectively). Everolimus strongly inhibited growth of the sensitive models in vivo but also significantly inhibited growth of the insensitive models, an effect attributable to its known anti-angiogenic/vascular properties. However, although tumor FDG and FLT uptake was significantly reduced in the sensitive models, it was not affected in the insensitive models, suggesting that endothelial-directed effects could not be detected by these PET tracers. Consistent with this hypothesis, in a well-vascularized orthotopic rat mammary tumor model, other antiangiogenic agents also failed to affect FDG uptake, despite inhibiting tumor growth. In contrast, the cytotoxic patupilone, a microtubule stabilizer, blocked tumor growth, and markedly reduced FDG uptake. These results suggest that FDG/FLT-PET may not be a suitable method for early markers of response to antiangiogenic agents and mTOR inhibitors in which anti-angiogenic/vascular effects predominate because the method could provide false-negative responses. These conclusions warrant clinical testing.
肿瘤的无创功能成像可以提供有价值的早期反应生物标志物，特别是对于靶向化疗。我们使用各种实验肿瘤模型，研究了正电子发射断层扫描（PET）测量 2-脱氧-2-[[18]F]氟葡萄糖（FDG）和 3'-脱氧-3'-[[18]F]氟胸苷（FLT）的能力，以检测对变构哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂依维莫司的反应。根据体外增殖抑制的 IC（50）值（浓度抑制细胞生长 50%），将肿瘤模型分类为敏感（鼠黑色素瘤 B16/BL6 和人肺癌 H596）或相对不敏感（人结肠 HCT116 和宫颈 KB31），分别为（<10 nM 和>1 microM）。依维莫司强烈抑制体内敏感模型的生长，但也显著抑制不敏感模型的生长，这一作用归因于其已知的抗血管生成/血管特性。然而，尽管敏感模型中的肿瘤 FDG 和 FLT 摄取显著减少，但在不敏感模型中没有受到影响，这表明内皮定向效应不能通过这些 PET 示踪剂检测到。与这一假设一致，在一个血管丰富的原位大鼠乳腺肿瘤模型中，其他抗血管生成剂也不能影响 FDG 的摄取，尽管它们抑制了肿瘤的生长。相比之下，细胞毒性药物 patupilone（一种微管稳定剂）抑制肿瘤生长，并显著减少 FDG 的摄取。这些结果表明，FDG/FLT-PET 可能不是一种适合用于抗血管生成剂和 mTOR 抑制剂早期反应标志物的方法，因为抗血管生成/血管效应占主导地位，这种方法可能会提供假阴性反应。这些结论需要临床测试。
