Rudin Markus, McSheehy Paul M J, Allegrini Peter R, Rausch Martin, Baumann Diana, Becquet Mike, Brecht Karin, Brueggen Josef, Ferretti Stephane, Schaeffer Fabienne, Schnell Christian, Wood Jeanette
Discovery Technology, Novartis Pharma AG, CH-4002 Basel, Switzerland.
NMR Biomed. 2005 Aug;18(5):308-21. doi: 10.1002/nbm.961.
Assessment of tumour vascularity may characterize malignancy as well as predict responsiveness to anti-angiogenic therapy. Non-invasive measurement of tumour perfusion and blood vessel permeability assessed as the transfer constant, K(trans), can be provided by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Using the orthotopic murine tumour model B16/BL6 melanoma, the small contrast agent GdDOTA (DOTAREM(R); Guerbet, Paris) was applied to assess the vascular transfer constant, K(trans), and interstitial leakage space, whereas intravascular iron oxide nanoparticles (Endorem(R); Guerbet, Paris) were used to detect relative tumour blood volume (rTBV), and in one experiment blood flow index (BFI). No correlations were observed between these four parameters (r(2) always <0.05). The B16/BL6 primary tumour and lymph-node cervical (neck) metastases produced high levels of the permeability/growth factor, VEGF. To probe the model, the novel VEGF receptor (VEGF-R) tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK) was tested for anti-tumour efficacy and its effects on DCE-MRI measured parameters of tumour vascularity. Data from the non-invasive measure of tumour vascularity were compared with a histological measurement of vasculature using the DNA-staining dye H33342. PTK/ZK inhibited growth of the primary and, particularly, cervical tumour metastases following chronic treatment for 2 weeks (50 or 100 mg/kg daily) of 1-week-old tumours, or with 1 week of treatment against more established (2-week-old) tumours. After chronic treatment with PTK/ZK, DCE-MRI detected significant decreases in K(trans) and interstitial leakage space, but not rTBV of both primary tumours and cervical metastases. Histological data at this time-point showed a significant decrease in blood vessel density of the cervical metastases but not the primary tumours. However, in the cervical metastases, the mean blood vessel width was increased by 38%, suggesting overall no marked change in blood volume. After acute (2-4 day) treatment, DCE-MRI of the cervical metastases demonstrated a significant decrease in K(trans) and interstitial leakage space and also in the initial area under the enhancement curve for GdDOTA (IAUC), but no change in the rTBV or BFI. Thus, significant changes could be detected in the DCE-MRI measurement of tumour uptake of a small contrast agent prior to changes in tumour size, which suggests that DCE-MRI could be applied in the clinic as a rapid and sensitive biomarker for the effects of VEGF-R inhibition on tumour blood vessel permeability and thus may provide an early marker for eventual tumour response.
评估肿瘤血管生成情况不仅可以对恶性肿瘤进行特征描述，还能预测对抗血管生成疗法的反应。动态对比增强磁共振成像（DCE-MRI）可提供肿瘤灌注和血管通透性的无创测量，以转移常数K(trans)来评估。使用原位小鼠肿瘤模型B16/BL6黑色素瘤，应用小分子造影剂钆喷酸葡胺（DOTAREM(R)；Guerbet公司，巴黎）来评估血管转移常数K(trans)和组织间隙渗漏空间，而血管内氧化铁纳米颗粒（Endorem(R)；Guerbet公司，巴黎）则用于检测相对肿瘤血容量（rTBV），并且在一项实验中还检测了血流指数（BFI）。这四个参数之间未观察到相关性（r(2)始终<0.05）。B16/BL6原发性肿瘤和颈部淋巴结转移瘤产生高水平的通透性/生长因子血管内皮生长因子（VEGF）。为了探究该模型，测试了新型VEGF受体（VEGF-R）酪氨酸激酶抑制剂PTK787/ZK222584（PTK/ZK）的抗肿瘤疗效及其对DCE-MRI测量的肿瘤血管生成参数的影响。将肿瘤血管生成的无创测量数据与使用DNA染色染料H33342对脉管系统进行的组织学测量数据进行比较。对于1周龄的肿瘤进行为期2周（每日50或100 mg/kg）的慢性治疗，或者对于更成熟（2周龄）的肿瘤进行为期1周的治疗后，PTK/ZK抑制了原发性肿瘤尤其是颈部肿瘤转移灶的生长。PTK/ZK慢性治疗后，DCE-MRI检测到原发性肿瘤和颈部转移瘤的K(trans)和组织间隙渗漏空间均显著降低，但rTBV未降低。此时的组织学数据显示颈部转移瘤的血管密度显著降低，但原发性肿瘤未降低。然而，在颈部转移瘤中，平均血管宽度增加了38%，这表明总体血容量没有明显变化。急性（2 - 4天）治疗后，颈部转移瘤的DCE-MRI显示K(trans)、组织间隙渗漏空间以及钆喷酸葡胺增强曲线下的初始面积（IAUC）均显著降低，但rTBV或BFI没有变化。因此，在肿瘤大小发生变化之前，DCE-MRI测量的小分子造影剂肿瘤摄取情况就可以检测到显著变化，这表明DCE-MRI可作为临床上一种快速且敏感的生物标志物，用于评估VEGF-R抑制对肿瘤血管通透性的影响，从而可能为最终的肿瘤反应提供早期标志物。
