E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma
E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma
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DOI：
10.1038/cgt.2011.79
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发表时间：
2012-02-01
影响因子：
6.4
通讯作者：
Shirakawa, T.
中科院分区：
文献类型：
--
作者：
Adhim, Z.;Lin, X.;Shirakawa, T.
大多数癌症化疗剂以最大耐受剂量（MTD）在短周期内给药，并中断治疗。然而，基于MTD的化疗通常与显著的毒性相关，并且治疗中断允许肿瘤再生长和获得化学抗性的机会。为了最大限度地减少这些缺点，许多研究人员建议采用节拍策略，其中化疗药物以显著低于MTD的剂量给药，而不中断治疗。节拍化疗的抗肿瘤作用可能部分是由于抑制肿瘤血管生成，它可以通过联合治疗，包括抗血管生成药物增强。在这项研究中，我们评估了E10A，携带内皮抑素基因的腺病毒，肿瘤血管生成的最有效的抑制剂，与每周低剂量顺铂在头颈部鳞状细胞癌异种移植小鼠模型中的协同作用。E10A体外诱导H891细胞内皮抑素mRNA和蛋白表达。E10A显著增强顺铂的体内肿瘤生长抑制作用。TUNEL（末端脱氧核苷酸转移酶介导的缺口末端标记）和抗CD31抗体的免疫组织化学分析显示，E10A和顺铂的组合诱导高水平的细胞凋亡和抑制肿瘤血管生成。重要的是，E10A使肿瘤中的铂浓度增加到单独顺铂诱导的5倍。Cancer Gene Therapy（2012）19，144 - 152; doi：10.1038/cgt.2011.79; 2011年11月25日在线发表
Most cancer chemotherapeutic agents are administered at the maximum-tolerated dose (MTD) in short cycles with treatment breaks. However, MTD-based chemotherapies are often associated with significant toxicity and treatment breaks allow the opportunity for tumor regrowth and acquisition of chemoresistance. To minimize these drawbacks, a metronomic strategy, in which chemotherapeutics are administered at doses significantly below the MTD without treatment breaks, has been suggested by many investigators. The antitumor effect of metronomic chemotherapy may be partially due to inhibition of tumor angiogenesis, and it could be enhanced by a combination therapy, including antiangiogenic agents. In this study, we evaluated the synergistic effect of E10A, an adenovirus carrying the endostatin gene, the most potent inhibitors of tumor angiogenesis, in combination with weekly low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. The E10A induced mRNA and protein expressions of endostatin in H891 cells in vitro. E10A significantly enhanced the in vivo tumor growth inhibitory effect of cisplatin. Immunohistochemical analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay and anti-CD31 antibodies revealed that the combination of E10A and cisplatin induced high levels of cell apoptosis and inhibited tumor angiogenesis. Importantly, E10A increased the platinum concentrations in tumors to fivefold higher than that induced by cisplatin alone. Cancer Gene Therapy (2012) 19, 144-152; doi: 10.1038/cgt.2011.79; published online 25 November 2011