抗新生血管内皮细胞单克隆抗体BVE-1治疗实体瘤的实验研究

Experimental study of the therapeutic effects of an anti endothelial cell monoclonal antibody BVE 1 for solid tumor xenograft in nude mice

目的研究以肿瘤新生血管为靶，用抗血管内皮细胞单克隆抗体治疗实体肿瘤的可行性。方法裸小鼠移植人平滑肌肉瘤细胞，人肝癌细胞及人胰腺癌细胞，以抗血管内皮细胞的单克隆抗体ＢＶＥ１或１３１Ｉ标记抗体ＢＶＥ１腹腔给药，并与正常鼠ＩｇＧ及１３１ＩＩｇＧ治疗对比，观察肿瘤体积变化，死后及活杀鼠进行病理学检查，计算瘤内微血管密度。结果肝癌、胰腺癌、平滑肌肉瘤组经抗体ＢＶＥ１治疗后，抑瘤率分别为７０．５％、４８．７％和４９．８％，并抑制了平滑肌肉瘤转移和降低了死亡率。１３１Ｉ标记抗体ＢＶＥ１治疗组一次给药后抑瘤率达８６．６％～８２．２％，抑瘤生长率较单纯抗体组明显提高。病理检查证实，抗体ＢＶＥ１治疗组肿瘤区毛细血管管壁变性，管腔阻塞，周围肿瘤细胞大片坏死。瘤内微血管密度明显低于未治疗组及鼠ＩｇＧ组。结论抗增生血管内皮细胞抗体ＢＶＥ１具有杀伤及抑制肿瘤区血管内皮细胞生长作用，从而导致肿瘤区毛细血管阻塞，阻断血供，抑制了肿瘤生长和转移，降低了死亡率。以之为载体偶联核素可增强此作用。

Objective To study the possibility of targeting endothelial cells with monoclonal antibody for the therapy of solid tumors. Methods Leiomyosarcoma cell line SK LMS 1, liver cancer cell line 7721 and pancreatic cancer cell line SW1990 xenografts in nude mice were treated ip with an anti endothelial cell monoclonal antibody BVE 1 or 131 I labeled BVE 1, with normal mouse IgG or 131 I labeled IgG as controls. The tumor volume was measured at regular intervals following treatment. After sacrifice of the mice, the tumor was histologically examined and the intra tumoral microvessel density(TMVD) recorded. Results The tumor growth inhibition effects in mice treated with BVE 1 was 49.8% in SK LMS 1, 48.7% in SW1990 and 70.5% in 7721,respectively. Metastasis of leiomyosarcoma was also inhibited by the antibody treatment, leading to decreased death rate. This effect was enhanced when treated with 131 I labeled BVE 1 with an increase of tumor growth inhibition rate to 82.2%～86.6%. Pathologically, capillary endothelial cells degeneration, occlusion of capillaries and massive tumor cells necrosis around the degenerated vessels were observed in the BVE 1 treated mice. TMVD was significantly lower in the BVE 1 treated mice than that in mice treated with normal mouse IgG and in the untreated mice. Conclusion The monoclonal antibody against vascular endothelial cells BVE 1 is effective in the treatment of human cancer xeno transplanted in nude mice through the induction of capillary endothelial degeneration and vascular occlusion inside of the tumor. It can be used as a novel strategic approach in the treatment of human solid tumors.