Xie Yi, Hicks Martin J, Kaminsky Stephen M, Moore Malcolm A S, Crystal Ronald G, Rafii Arash
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States.
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
Gynecol Oncol. 2014 Nov;135(2):325-32. doi: 10.1016/j.ygyno.2014.07.105. Epub 2014 Aug 6.
Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer.
AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice.
The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p<0.05) and the area of blood vessels in the tumor was decreased (p<0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p<0.001). Administration of AAVrh10.BevMab 4days after A2780-luciferase cell implantation reduced tumor growth (p<0.01) and increased mouse survival (p<0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone.
A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model.
抗血管生成疗法，如贝伐单抗（一种抗血管内皮生长因子（VEGF）的单克隆抗体），已被用于治疗卵巢癌，但短暂且较低的腹膜药物水平可能是治疗失败的一个因素。我们推测，单次给予腺相关病毒（AAV）介导的腹膜内表达贝伐单抗可实现持续表达，并抑制卵巢癌的生长和转移。
AAVrh.10BevMab是一种编码贝伐单抗的恒河猴10型腺相关病毒载体，在裸免疫缺陷小鼠的人卵巢癌细胞腹膜种植模型中，评估单次腹膜内给药持续抑制腹膜肿瘤生长的能力。
数据表明，在小鼠单次腹膜内给药后，AAVrh10.BevMab可在腹膜腔内介导贝伐单抗的持续高水平表达。在接受AAVrh10.BevMab治疗的携带A2780人卵巢癌的小鼠中，肿瘤生长受到显著抑制（p<0.05），肿瘤内血管面积减小（p<0.04）。在存在AAVrh10.BevMab的情况下，携带A2780异种移植瘤或SK-OV3异种移植瘤的小鼠生存期显著延长（p<0.001）。在A2780-荧光素酶细胞植入后4天给予AAVrh10.BevMab可减少肿瘤生长（p<0.01）并提高小鼠生存率（p<0.0001）。事实证明，AAVrh10.BevMab与细胞毒性试剂紫杉醇或拓扑替康联合使用在提高生存率方面比单独使用细胞毒性试剂更有效。
单次给予AAVrh10.BevMab可在腹膜腔内提供贝伐单抗持续且高水平的局部表达，并显著抑制腹膜种植转移，提高卵巢癌小鼠模型的生存率。
