Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)
Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)
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DOI：
10.1038/80466
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发表时间：
2000-10-01
期刊：
影响因子：
82.9
通讯作者：
Korn, WM
中科院分区：
文献类型：
--
作者：
Ries, SJ;Brandts, CH;Korn, WM
腺病毒突变体dl 1520（ONYX-015）不表达结合并灭活p53的E1 B-55 K蛋白。该病毒在具有突变型p53的肿瘤细胞中复制，但在具有功能性p53的正常细胞中不复制。尽管肿瘤内注射dl 1520在实体瘤患者中显示出有希望的反应，但先前的体外研究尚未建立p53状态与dl 1520复制之间的密切相关性。在这里，我们确定损失的p14（ARF）作为一种机制，允许dl 1520复制保留野生型p53的肿瘤细胞。我们证明，重新引入p14（ARF）到肿瘤细胞与野生型p53抑制复制的dl 1520在p53依赖的方式。我们的研究支持dl 1520在p53通路内病变而不是p53突变的肿瘤中的治疗用途。
The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14(ARF) as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14(ARF) into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.