McCrudden Kimberly W, Hopkins Benjamin, Frischer Jason, Novikov Anna, Huang Jianzhong, Kadenhe Angela, New Tamara, Yokoi Akiko, Yamashiro Darrell J, Kandel Jessica J, Middlesworth William
Division of Pediatric Surgery, Children's Hospital of New York-Presbyterian, Columbia University, New York, New York 10032, USA.
J Pediatr Surg. 2003 Mar;38(3):308-14; discussion 308-14. doi: 10.1053/jpsu.2003.50099.
Hepatoblastoma is the most common primary hepatic malignancy of childhood, frequently presenting as advanced disease. Vascular endothelial growth factor (VEGF) is an endothelial mitogen and survival factor critical to growth and angiogenesis in many human cancers. Inhibition of VEGF effectively suppresses tumorigenesis in multiple experimental models. The authors hypothesized that anti-VEGF antibody would alter vascular architecture and impede tumor growth in experimental hepatoblastoma.
The Institutional Animal Care and Use Committee of Columbia University approved all protocols. Xenografts were established in athymic mice by intrarenal injection of cultured human hepatoblastoma cells. Anti-VEGF antibody (100 microg/dose) or vehicle was administered intraperitoneally 2 times per week for 5 weeks. At week 6, 10 control/treated mice were killed and remaining animals maintained without treatment until week 8. Tumor weights were compared by Kruskal-Wallis analysis, and vascular alterations ascertained by fluorescein angiography and specific immunostaining.
Anti-VEGF antibody significantly inhibited tumor growth at 6 weeks (1.85 g +/- 0.60 control, 0.05 +/- 0.03 antibody, P <.0003). In comparison with controls, treated xenografts showed decreased vascularity and dilated surviving vessels with prominent vascular smooth muscle elements.
Specific anti-VEGF therapy inhibits neoangiogenesis and significantly suppresses tumor growth in experimental hepatoblastoma. Surviving vasculature displays dilation and increased vascular smooth muscle. Anti-VEGF agents may represent new therapeutic alternatives for children with advanced disease.
肝母细胞瘤是儿童最常见的原发性肝脏恶性肿瘤，常表现为进展期疾病。血管内皮生长因子（VEGF）是一种内皮细胞有丝分裂原和存活因子，对许多人类癌症的生长和血管生成至关重要。在多个实验模型中，抑制VEGF可有效抑制肿瘤发生。作者推测抗VEGF抗体可改变实验性肝母细胞瘤的血管结构并阻碍肿瘤生长。
哥伦比亚大学机构动物护理和使用委员会批准了所有方案。通过肾内注射培养的人肝母细胞瘤细胞在无胸腺小鼠中建立异种移植模型。抗VEGF抗体（100μg/剂量）或赋形剂每周腹腔注射2次，共5周。在第6周时，处死10只对照/治疗小鼠，其余动物不进行治疗直至第8周。通过Kruskal-Wallis分析比较肿瘤重量，并通过荧光素血管造影和特异性免疫染色确定血管改变。
抗VEGF抗体在6周时显著抑制肿瘤生长（对照组1.85g±0.60，抗体组0.05±0.03，P<.0003）。与对照组相比，治疗后的异种移植瘤血管减少，存活血管扩张，血管平滑肌成分突出。
特异性抗VEGF治疗可抑制实验性肝母细胞瘤中的新生血管形成并显著抑制肿瘤生长。存活的脉管系统表现为扩张和血管平滑肌增加。抗VEGF药物可能为患有进展期疾病的儿童提供新的治疗选择。
