Hay J G, Shapiro N, Sauthoff H, Heitner S, Phupakdi W, Rom W N
Department of Medicine, New York University Medical Center, NY 10016, USA.
Hum Gene Ther. 1999 Mar 1;10(4):579-90. doi: 10.1089/10430349950018652.
It has been proposed that an adenovirus with the E1b-55kD gene deleted has a selective advantage in replicating in cancer cells that have mutations in the p53 gene (Bischoff et al., 1996). We have explored this hypothesis in several lung cancer cell lines, and evaluated potential mechanisms that might regulate the replication of Ad338, an E1b-55kD-deleted virus, with the objective of developing a rational approach for targeting gene therapy to lung tumors. Our data show that Ad338 replicates poorly in three lung cancer cell lines with various p53 mutations (H441, H446, and Calu1), yet this virus replicates to a high level in a lung cancer cell line with wild-type p53 (A549) and in a normal lung fibroblast line (IMR90). Viral DNA replication, expression of viral proteins, and shutoff of host cell proteins were not important variables in limiting the replication of the E1b-55kD-deleted virus. However, the cell lines resistant to host cell protein shutoff were also the most resistant to the cytopathic effect induced by mutant and wild-type virus and the only cells to survive for 8 days following infection. The E1b-55kD protein clearly has an important role in viral replication beyond its interaction with p53. Thus, an E1b-55kD-deleted virus cannot be used to specifically target viral replication to p53-mutated lung cancer cells.
有人提出，缺失E1b - 55kD基因的腺病毒在p53基因发生突变的癌细胞中复制具有选择性优势（比肖夫等人，1996年）。我们在几种肺癌细胞系中探讨了这一假说，并评估了可能调节Ad338（一种缺失E1b - 55kD的病毒）复制的潜在机制，目的是开发一种将基因治疗靶向肺肿瘤的合理方法。我们的数据表明，Ad338在三种具有不同p53突变的肺癌细胞系（H441、H446和Calu1）中复制不佳，但这种病毒在具有野生型p53的肺癌细胞系（A549）和正常肺成纤维细胞系（IMR90）中能高水平复制。病毒DNA复制、病毒蛋白表达以及宿主细胞蛋白的关闭不是限制缺失E1b - 55kD病毒复制的重要变量。然而，对宿主细胞蛋白关闭具有抗性的细胞系对突变型和野生型病毒诱导的细胞病变效应也最具抗性，并且是感染后唯一存活8天的细胞。E1b - 55kD蛋白显然在病毒复制中具有重要作用，不仅仅是其与p53的相互作用。因此，缺失E1b - 55kD的病毒不能用于将病毒复制特异性靶向p53突变的肺癌细胞。
