AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer
AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer
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DOI：
10.1038/gt.2010.118
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发表时间：
2011-02-01
期刊：
影响因子：
5.1
通讯作者：
Ramakrishnan, S.
中科院分区：
文献类型：
--
作者：
Subramanian, I. V.;Devineni, S.;Ramakrishnan, S.
内皮抑素增强紫杉醇（taxol）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内皮细胞显示多极纺锤体和核分叶，导致有丝分裂灾难和细胞死亡。发现核异常的诱导依赖于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了联合治疗的效果。肌内注射重组腺相关病毒2型诱导p125a -内皮抑素持续表达。体内研究表明，联合治疗抑制了乳腺癌的生长，延缓了多灶性乳腺腺癌的发病，减少了肿瘤血管生成，提高了治疗小鼠的存活率。在第二个模型中，雌性胸腺小鼠被原位移植了转移的人类乳腺癌细胞系。抗血管生成基因治疗联合紫杉醇可抑制肿瘤血管生成和肺/淋巴结转移。这些研究表明，内皮抑素基因治疗和化疗共同抑制肿瘤的发生、生长和转移。基因治疗（2011）18,145-154；doi: 10.1038 / gt.2010.118;2010年9月16日在线发布
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 beta-catenin levels as wnt-mediated overexpression of beta-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. Gene Therapy (2011) 18, 145-154; doi:10.1038/gt.2010.118; published online 16 September 2010