目的 探讨蝎毒多肽增强5-氟尿嘧啶（5-Fu）抑制肿瘤血管生成的机制。方法 建立H₂₂肝癌皮下荷瘤模型，随机分为模型组、蝎毒多肽（20 mg/kg）组、5-Fu（20 mg/kg）组、联合组（5-Fu＋蝎毒多肽），每组20只。绘制肿瘤体积增长曲线并计算抑瘤率；免疫组织化学法检测各组肿瘤组织微血管密度（MVD）、PTEN、PI3K、P-Akt、缺氧诱导因子-1α（HIF-1α）的变化；Western blotting检测各组肿瘤组织中PTEN、PI3K、P-Akt、HIF-1α蛋白的表达。结果 联合组、5-Fu组、蝎毒多肽组H₂₂肝癌移植瘤的生长较模型组均受到明显抑制（P＜0.05），联合组和5-Fu组瘤质量和肿瘤体积差异亦显著（P＜0.05）。与荷瘤对照组相比，联合组明显下调PI3K、P-Akt、HIF-1α表达（P＜0.01），上调PTEN表达（P＜0.01），降低MVD（P＜0.01）。结论 蝎毒多肽可促进5-Fu抑制小鼠H₂₂肝癌移植瘤血管生成，其机制可能与抑制肿瘤微环境中PI3K、P-Akt、HIF-1α的表达，上调PTEN的表达有关。

Objective To explore the inhibitory effects of polypeptide from scorpion venom (PSV) combined with 5-fluorouracil (5-Fu) on angiogenesis of H₂₂ hepatoma in mice and its mechanism. Methods The H₂₂ hepatoma tumor model was established by sc implanting H₂₂ hepatoma cells into mice. The tumor-bearing mice were randomly divided into four groups: control , PSV (20 mg/kg), 5-Fu (20 mg/kg), and combination groups, 10 mice in each group. The effect of PSV on tumor growth was observed by recording tumor growth curve and calculating the inhibitory rate; Immunohistochemistry was applied to detecting microvessel density (MVD), the levels of PTEN, PI3K, P-Akt, and hypoxia-inducible factor-1α (HIF-1α) in tumor tissue of mice in each group; Western blotting was applied to detecting the expression of PTEN, PI3K, P-Akt, and HIF-1α in tumor tissue of mice in each group. Results The growth of H₂₂ hepatoma transplantation tumor was inhibited more obviously in the combination group, the 5-Fu group and PSV group than that in the H₂₂ hepatoma tumor model group (P < 0.05). There was statistical difference in the tumor weight and the tumor volume between the combination and the 5-Fu groups (P < 0.05). Compared with the control group, the protein expression of PI3K, P-Akt, and HIF-1α significantly decreased while the protein expression of PTEN significantly increased in the combination group (P < 0.01). The MVD was obviously lower in the combination group than that in the control and 5-Fu groups (P < 0.01). Conclusion PSV combined with 5-Fu could inhibit the angiogenesis of H₂₂ hepatoma transplantation tumor in mice. Its mechanisms might be associated with inhibiting the expression of PI3K, P-Akt, and HIF-1α and increasing PTEN in the microenvironment of tumors.

基金项目：国家自然科学基金资助项目（81073102，30873408）；山东省自然科学基金资助项目（ZR2010HQ003）