Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination.
Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination.
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DOI：
10.1038/cgt.2009.44
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发表时间：
2010-01
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
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尽管卵巢癌的化疗在过去几十年中取得了巨大的发展，但晚期腹膜播散病例的预后仍不令人满意，迫切需要联合收割机与化疗相结合的新治疗方式。我们最近开发了使用端粒酶特异性复制选择性腺病毒（Telomelysin：OBP-301）治疗实体瘤的病毒疗法，其中人端粒酶逆转录酶（hTERT）基因启动子已插入到指导肿瘤特异性E1基因表达。在这项研究中，我们研究了OBP-301联合顺铂（CDDP）对卵巢癌细胞的抗肿瘤作用。OBP-301以0.01-100的感染复数（MOI）体外处理SKOV 3细胞以剂量依赖性方式诱导显著的细胞死亡，在MOI为1-10时具有中度细胞毒性，在MOI为100时具有最大细胞毒性。相比之下，正常人细胞的OBP-301处理在1-10的MOI下没有显示出显著的细胞死亡，并且在100的MOI下显示出适度的细胞毒性。0.5-1 μM的低剂量CDDP仅诱导20%的细胞死亡，与MOI为1-10的OBP-301组合显著增强了CDDP的作用，最终达到40%的细胞死亡。这种CDDP敏感性的增强也在CDDP耐药的卵巢癌细胞中观察到。使用具有腹膜播散的SK 0 V3异种移植小鼠模型进一步测试组合效应。在腹腔内施用OBP-301后，我们证实了注射的与绿色荧光蛋白（GFP）基因（OBP-401）融合的OBP-301优先定位于腹膜播散，如通过荧光成像所确定的。用低剂量（0.5 mg kg-1）的CDDP处理小鼠具有适度的效果，显示传播减少10%，而以MOI 10腹腔内给予OBP-301导致增强的效果，实现传播减少约80%。Kaplan-Meier分析显示，与单独的CDDP相比，用CDDP加OBP-301处理的小鼠的总体存活率提高。这些发现支持腹膜内施用OBP-301以使卵巢癌细胞对CDDP敏感的治疗潜力。
Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01–100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1–10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1–10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5–1 μM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1–10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg–1) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan–Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.
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影响因子：
6.4
作者：
Fujiwara, Toshiya;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
通讯作者：
Fujiwara, Toshiyoshi
影响因子：
4.8
作者：
Hayakawa, J;Ohmichi, M;Murata, Y
通讯作者：
Murata, Y
影响因子：
15.9
作者：
Kurihara, T;Brough, DE;Kufe, DW
通讯作者：
Kufe, DW
影响因子：
10.3
作者：
du Bois, A;Lück, HJ;Pfisterer, J
通讯作者：
Pfisterer, J
影响因子：
6.4
作者：
Hioki, Masayoshi;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
通讯作者：
Fujiwara, Toshiyoshi