Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene
Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene
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DOI：
10.1038/sj.cgt.7701110
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发表时间：
2008-02-01
影响因子：
6.4
通讯作者：
Bartlett, D. L.
中科院分区：
文献类型：
--
作者：
Chalikonda, S.;Kivlen, M. H.;Bartlett, D. L.
在这项研究中，我们评估了携带酵母胞嘧啶脱氨酶基因的高肿瘤选择性溶瘤痘苗病毒在体外和体内感染和裂解人和小鼠卵巢肿瘤的能力。病毒vvDD-CD在体外可感染、复制人和小鼠卵巢癌细胞，并能有效地杀伤人和小鼠卵巢癌细胞。在涉及小鼠MOSEC或人类A2780卵巢癌模型的两种不同治疗方案中，区域递送vvDD-CD选择性地靶向肿瘤细胞和卵巢组织，有效地延缓肿瘤或腹水的发展，并带来显著的生存优势。使用vvDD-CD与前药5-氟胞嘧啶联合使用的溶瘤病毒疗法为荷瘤免疫活性小鼠带来了额外的长期生存优势。这些发现表明，肿瘤选择性溶瘤疫苗联合基因导向的酶前药疗法是治疗同基因小鼠和人类异种移植模型中晚期卵巢癌的一种高效策略。鉴于这种武装溶瘤病毒的生物安全性、肿瘤选择性和溶瘤能力，这种双重疗法值得进一步研究，作为一种有前途的转移性卵巢癌新疗法。
In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer.