Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer.
Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-14-0463
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Kaur B
中科院分区：
文献类型：
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作者：
Bolyard C;Yoo JY;Wang PY;Saini U;Rath KS;Cripe TP;Zhang J;Selvendiran K;Kaur B
需要新的治疗方案来改善与晚期卵巢癌相关的令人沮丧的结果。溶瘤病毒目前正在卵巢癌患者中进行测试。在这里，我们测试了多柔比星与34.5ENVE组合的治疗效果，34.5ENVE是一种溶瘤性单纯疱疹病毒，由修饰的干细胞特异性巢蛋白启动子转录驱动，编码抗血管生成血管抑素-120（VStat 120），用于治疗进行性卵巢癌。通过标准MTT测定法在卵巢癌细胞系、小鼠腹水来源的肿瘤细胞和原发性患者腹水来源的肿瘤细胞中评估34.5ENVE的抗肿瘤功效。用transwell小室法检测34. 5ENVE感染卵巢癌细胞的条件培养液对内皮细胞迁移的抑制作用。使用Chou-Talalay协同分析评价34.5ENVE和阿霉素之间的细胞毒性相互作用的范围。评价病毒复制、HSV受体表达和细胞凋亡。在人卵巢癌的鼠异种移植模型中体内评价溶瘤病毒疗法与多柔比星组合的功效。用34.5ENVE处理降低了卵巢癌细胞系以及小鼠腹水衍生的和患者腹水衍生的卵巢肿瘤细胞的细胞活力。用34.5ENVE感染的肿瘤细胞的条件培养基减少了内皮细胞迁移。当与多柔比星组合时，34.5ENVE协同地杀死半胱天冬酶-3/7活化的显著增加和亚G1细胞群体的增加。阿霉素和34.5ENVE的组合显著延长了荷腹膜内卵巢癌肿瘤的裸鼠的生存期。该研究表明34.5ENVE单独使用以及与多柔比星联合使用对播散性腹膜卵巢癌具有显著的抗肿瘤疗效。
Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell-specific nestin promoter, and encoding for anti-angiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. Anti-tumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites-derived tumor cells, and primary patient ascites-derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou-Talalay synergy analysis. Viral replication, HSV receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites-derived and patient ascites-derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer.