Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.
Br J Cancer. 2012 Aug 7;107(4):658-66. doi: 10.1038/bjc.2012.322. Epub 2012 Jul 17.
The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficiency of available treatments have raised the need for alternative curative strategies. We aimed to assess the therapeutic potential of TL-118, a new anti-angiogenic drug combination, for CRLM treatment, in a mouse model.
The therapeutic potential of TL-118 was evaluated and compared with B20-4.1.1 (B20; anti-VEGF antibody) and rapamycin in CRLM-bearing mice. Tumour progression and the vascular changes were monitored by MRI. Additionally, mice survival, cell proliferation, apoptosis and vessel density were evaluated.
This study demonstrated an unequivocal advantage to TL-118 therapy by significantly prolonging survival (threefold) and reducing metastasis perfusion and vessel density (ninefold). The underlying mechanism for TL-118-treatment success was associated with hepatic perfusion attenuation resulting from reduced nitric-oxide (NO) serum levels as elucidated by using hemodynamic response imaging (HRI, a functional MRI combined with hypercapnia and hyperoxia). Further, systemic hepatic perfusion reduction during the initial treatment phase by adding NO inhibitor has proven to be essential for reaching maximal therapeutic effects for both TL-118 and B20.
TL-118 harbours a potential clinical benefit to CLRM patients. Moreover, the reduction of hepatic perfusion at early stages of anti-angiogenic therapies by adding NO inhibitor is crucial for achieving maximal anti-tumour effects.
结直肠癌肝转移（CRLM）患者的预后较差，可用的治疗方法有限，这使得人们需要寻找替代的治疗策略。本研究旨在评估 TL-118（一种新型抗血管生成药物组合）在结直肠癌肝转移模型中的治疗潜力。
评估了 TL-118 与 B20-4.1.1（B20；抗 VEGF 抗体）和雷帕霉素在结直肠癌肝转移小鼠模型中的治疗潜力，并进行了比较。通过 MRI 监测肿瘤进展和血管变化。此外，还评估了小鼠的存活率、细胞增殖、凋亡和血管密度。
这项研究表明，TL-118 治疗具有明显优势，可显著延长生存时间（三倍），减少转移灌注和血管密度（九倍）。TL-118 治疗成功的潜在机制与肝脏灌注减弱有关，这是由于血清一氧化氮（NO）水平降低所致，这一点通过血流动力学反应成像（HRI，一种结合高碳酸血症和高氧的功能性 MRI）得到了阐明。此外，在初始治疗阶段通过添加 NO 抑制剂来减少全身肝灌注对于达到 TL-118 和 B20 的最大治疗效果至关重要。
TL-118 对结直肠癌肝转移患者具有潜在的临床获益。此外，在抗血管生成治疗的早期阶段通过添加 NO 抑制剂来减少肝灌注对于达到最大抗肿瘤效果至关重要。
