Department of Obstetrics and Gynecology and Women's Health, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Gene Ther. 2011 Feb;18(2):145-54. doi: 10.1038/gt.2010.118. Epub 2010 Sep 16.
Endostatin potentiates the antimitotic effects of paclitaxel (taxol) on endothelial cells (ECs). P125A-endostatin and taxol-treated ECs showed multipolar spindles and nuclear lobulation, leading to mitotic catastrophe and cell death. Induction of nuclear abnormalities was found to be dependent on β-catenin levels as wnt-mediated overexpression of β-catenin reversed the changes in nuclear morphology. These results prompted us to investigate whether antiangiogenic gene therapy and paclitaxel chemotherapy can synergistically inhibit angiogenesis and tumor growth. We first determined the effect of combination treatment in a transgenic mouse model of breast cancer. Intramuscular injection of recombinant adeno-associated virus type-2 virus induced sustained expression of P125A-endostatin. In vivo studies showed that combination therapy inhibited mammary cancer growth, delayed the onset of multifocal mammary adenocarcinomas, decreased tumor angiogenesis and increased survival in treated mice. In a second model, female athymic mice were orthotopically transplanted with a metastatic human breast cancer cell line. Antiangiogenic gene therapy in combination with paclitaxel inhibited tumor angiogenesis and lung/lymph-node metastasis in this model. These studies demonstrate cooperation between endostatin gene therapy and chemotherapy to inhibit tumor initiation, growth and metastasis.
内皮抑素增强紫杉醇（泰素）对内皮细胞（ECs）的抗有丝分裂作用。P125A 内皮抑素和紫杉醇处理的 ECs 表现出多极纺锤体和核分叶，导致有丝分裂灾难和细胞死亡。核异常的诱导被发现依赖于β-连环蛋白水平，因为 wnt 介导的β-连环蛋白过表达逆转了核形态的变化。这些结果促使我们研究抗血管生成基因治疗和紫杉醇化疗是否能协同抑制血管生成和肿瘤生长。我们首先在乳腺癌转基因小鼠模型中确定联合治疗的效果。重组腺相关病毒 2 型病毒的肌肉内注射诱导 P125A 内皮抑素的持续表达。体内研究表明，联合治疗抑制乳腺癌生长，延迟多灶性乳腺腺癌的发生，减少肿瘤血管生成，并增加治疗小鼠的存活率。在第二个模型中，雌性无胸腺小鼠被原位移植转移性人乳腺癌细胞系。抗血管生成基因治疗与紫杉醇联合抑制了该模型中的肿瘤血管生成和肺/淋巴结转移。这些研究表明内皮抑素基因治疗与化疗之间存在合作，以抑制肿瘤的起始、生长和转移。
