Targeting interferon-α increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus
Targeting interferon-α increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus
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DOI：
10.1038/sj.mt.6300064
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Doronin, Konstantin
中科院分区：
文献类型：
--
作者：
Shashkova, Elena V.;Spencer, Jacqueline F.;Doronin, Konstantin
需要新的方法来提高溶瘤腺病毒 (Ad) 的抗肿瘤效力并增加癌症特异性。我们假设干扰素-α (IFN-α) 表达与 Ad 的 e1a 基因中的特定突变相结合，可以将载体复制靶向 IFN-α 途径中的遗传缺陷，从而提高抗肿瘤功效并降低毒性。条件复制 Ad 载体 KD3-IFN 在 e1a 基因中携带 dl1101/1107 突变，消除了 E1A 蛋白与 p300/CBP 和 pRb 的结合。 KD3-IFN 在载体复制的同时表达人 IFN-α，并过表达腺病毒死亡蛋白（ADP；E3-11.6K）。在免疫缺陷小鼠的人肝细胞癌肿瘤和免疫功能正常的叙利亚仓鼠的仓鼠肾癌肿瘤中，KD3-IFN 的抗肿瘤活性显着高于对照载体。与癌细胞相比，dl1101/1107 突变使得正常细胞中的 Ad 复制对 IFN-α 的抗病毒作用敏感。这些结果转化为对 C57BL/6 小鼠全身给药后载体毒性降低。 Ad 溶瘤、ADP 过表达和 IFN-α 介导的免疫疗法的组合代表了提高复制 Ads 抗癌功效的三管齐下的方法。利用 dl1101/1107 突变为表达 IFN-α 的具有复制能力的 Ads 提供了额外的选择性机制。
Novel approaches are needed to improve the antitumor potency and to increase the cancer specificity of oncolytic adenoviruses ( Ad). We hypothesized that the combination of interferon-alpha (IFN-alpha) expression with a specific mutation in the e1a gene of Ad could target vector replication to genetic defects in the IFN-alpha pathway resulting in both improved antitumor efficacy and reduced toxicity. The conditionally replicative Ad vector KD3-IFN carries the dl1101/1107 mutation in the e1a gene that eliminates binding of E1A proteins to p300/CBP and pRb. KD3-IFN expresses human IFN-alpha in concurrence with vector replication and overexpresses the adenovirus death protein ( ADP; E3-11.6K). The antitumor activity of KD3-IFN was significantly higher than that of a control vector in established human hepatocellular carcinoma tumors in immunodeficient mice and in hamster kidney cancer tumors in immunocompetent Syrian hamsters. The dl1101/1107 mutation rendered Ad replication sensitive to the antiviral effect of IFN-alpha in normal as opposed to cancer cells. These results translated to reduced vector toxicity upon systemic administration to C57BL/6 mice. The combination of Ad oncolysis, ADP overexpression, and IFN-alpha-mediated immunotherapy represents a three-pronged approach for increasing the anticancer efficacy of replicative Ads. Exploiting the dl1101/1107 mutation provides a mechanism for additional selectivity of IFN-alpha-expressing replication-competent Ads.