Habib Nagy A, Mitry Ragai R, Sarraf Catherine E, Jiao Long R, Havlík Roman, Nicholls Joanna, Jensen Steen L
Department of Surgery, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Cancer Gene Ther. 2002 May;9(5):414-20. doi: 10.1038/sj.cgt.7700455.
E1B-deleted virus dl1520 (ONYX-015) has been previously used in clinical trials mainly for treatment of head and neck tumors, and has been shown to have beneficial effects independent of p53 status. The main aim of this investigation was to carry out a preclinical study for assessment of the use of dl1520 in in vitro and in vivo hepatocellular carcinoma (HCC) models with various p53 status (deleted, mutant, and wild type), and study the ultrastructural changes in the carcinoma cells during and following treatment with dl1520.
dl1520 (ONYX-015) virus was used for treatment of three HCC cell lines in culture, then for treatment of developed xenografts in SCID mice. The effects of dl1520 on HCC cell growth and accompanied morphological changes were assessed by various techniques including transmission electron microscopy. dl1520 infection was confirmed using polymerase chain reaction and immunolabeling at transmission electron microscopy level.
dl1520 was effective in killing cells and inhibiting HCC cell growth both in vitro and in vivo. The cell killing was at higher levels in cells possessing abnormal p53. Survival rates in SCID mice treated with dl1520 were statistically significantly higher in HCC tumors with deleted and mutant p53, than in tumors with wild-type p53.
The findings in this study suggest that dl1520 could be safely and effectively used for treatment of HCC dependent on the p53 status of the cells in vivo. Characteristic morphological changes that took place in the dl1520-treated HCC cells/tumors were distinct at transmission electron microscopy level and are the first of their kind to be reported.
E1B 缺失病毒 dl1520（ONYX - 015）此前主要用于头颈部肿瘤的临床试验，且已显示出与 p53 状态无关的有益效果。本研究的主要目的是开展一项临床前研究，以评估 dl1520 在具有不同 p53 状态（缺失、突变和野生型）的体外和体内肝细胞癌（HCC）模型中的应用，并研究 dl1520 治疗期间及治疗后癌细胞的超微结构变化。
使用 dl1520（ONYX - 015）病毒处理培养中的三种 HCC 细胞系，然后用于治疗 SCID 小鼠体内已形成的异种移植物。通过包括透射电子显微镜在内的各种技术评估 dl1520 对 HCC 细胞生长及伴随的形态学变化的影响。在透射电子显微镜水平上，使用聚合酶链反应和免疫标记确认 dl1520 感染。
dl1520 在体外和体内均能有效杀伤细胞并抑制 HCC 细胞生长。在具有异常 p53 的细胞中，细胞杀伤水平更高。用 dl1520 治疗的 SCID 小鼠中，p53 缺失和突变的 HCC 肿瘤的存活率在统计学上显著高于野生型 p53 的肿瘤。
本研究结果表明，dl1520 可根据体内细胞的 p53 状态安全有效地用于 HCC 的治疗。dl1520 处理的 HCC 细胞/肿瘤中发生的特征性形态学变化在透射电子显微镜水平上是独特的，且是首次报道此类变化。
