Liu Fengjun, Tan Gang, Li Jie, Dong Xuesong, Krissansen Geoffrey W, Sun Xueying
Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China.
Cancer Sci. 2007 Sep;98(9):1381-7. doi: 10.1111/j.1349-7006.2007.00542.x. Epub 2007 Jul 11.
Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death, and is chemoresistant to anticancer drugs. Anti-angiogenic therapy has been shown to enhance the efficacy of chemotherapy to treat solid tumors. The aim of the present study was to determine whether endostatin, a potent antiangiogenic agent, could enhance the efficacy of doxorubicin to combat HCC. An endostatin expression plasmid was constructed and its expression in vitro and in vivo was detected after gene transfer. Recombinant endostatin inhibited angiogenesis in the chorioallantoic membrane assay, and showed synergistic effects with doxorubicin in inhibiting the in vitro proliferation of endothelial cells, but not that of tumor cells. Both endostatin gene therapy and doxorubicin suppressed the growth of subcutaneous human HepG2 tumors established in BALB/c nude mice, and tumor angiogenesis. Combination therapy with endostatin gene therapy and doxorubicin showed a stronger effect in suppressing tumor growth, and tumor angiogenesis, than the respective monotherapies. Gene transfer of endostatin down-regulated the expression of both hypoxia-inducible factor-1alpha and vascular endothelial growth factor (VEGF), whereas doxorubicin only down-regulated VEGF expression. Endostatin and doxorubicin synergized to down-regulate VEGF expression. Endostatin and doxorubicin combination therapy warrants investigation as a therapeutic strategy to combat HCC.
肝细胞癌(HCC)是癌症相关最常见的死亡原因之一,并且对抗癌药物具有化学抗性。抗血管生成疗法已被证明可增强化疗治疗实体瘤的疗效。本研究的目的是确定强效抗血管生成剂内皮抑素是否能增强阿霉素对抗HCC的疗效。构建了内皮抑素表达质粒,并在基因转移后检测其在体内外的表达。重组内皮抑素在鸡胚绒毛尿囊膜试验中抑制血管生成,并在抑制内皮细胞而非肿瘤细胞的体外增殖方面与阿霉素显示出协同作用。内皮抑素基因治疗和阿霉素均抑制了在BALB/c裸鼠中建立的皮下人HepG2肿瘤的生长以及肿瘤血管生成。内皮抑素基因治疗与阿霉素联合治疗在抑制肿瘤生长和肿瘤血管生成方面比各自的单一疗法显示出更强的效果。内皮抑素的基因转移下调了缺氧诱导因子-1α和血管内皮生长因子(VEGF)的表达,而阿霉素仅下调VEGF的表达。内皮抑素和阿霉素协同下调VEGF表达。内皮抑素与阿霉素联合治疗作为对抗HCC的治疗策略值得研究。