PURPOSEThe potent anticancer efficacy of oncolytic viruses has been verified in Clinic in recent years. Cisplatin (DDP) is one of most common chemotherapeutic drugs, but is accompanied by side effects and drug resistance. Our previous studies have shown the strategy of cancer -targeting gene-viro-therapy (CTGVT) mediated by the oncolytic virus ZD55 containing the XAF1 cDNA (ZD55-XAF1), which exhibited potent antitumor effects in various tumor cells and no apparent toxicities on normal cells. In the study, the CTGVT strategy is broadened by combining DDP with ZD55-XAF1 for growth inhibition of hepatocellular carcinoma (HCC) cells.METHODSThe transgenic expression was evaluated by both in vitro and in vivo experiments, and the enhanced inhibitory effect of ZD55-XAF1 combined with cisplatin was assessed in HCC cells. The cytotoxicity on normal liver cells was evaluated by MTT assay and apoptotic cell staining. Activation of caspase-9 and PARP for apoptosis was further detected by Western blot analysis. The in vivo antitumor efficacy of combination treatment with cisplatin and ZD55-XAF1 was estimated in an HCC xenograft mouse model.RESULTSWe found that the combination of ZD55-XAF1 and cisplatin showed enhanced inhibitory effects on the proliferation of HCC cells in vitro and tumor growth in mice. Furthermore, the combined treatment of ZD55-XAF1 and DDP decreases the chemotherapy dose needed to achieve the same inhibitory effect without overlapping toxicities on normal liver cells and induces tumor cell apoptosis via the activation of caspase-9/PARP pathway.CONCLUSIONThus, these data suggest that the chemo-gene-viro-therapeutic strategy by combining ZD55-XAF1 and DDP reveals a novel therapeutic strategy for hepatocellular carcinoma.

2008-01-01·Tumor Biology

XIAP-Associated Factor 1 (XAF1) Suppresses Angiogenesis in Mouse Endothelial Cells

Article

作者: Li, Zesong ; Shen, Zan ; Dai, Yun ; Gu, Qing ; Wong, Benjamin C. Y. ; Qi, Rong ; Zou, Bing ; Ma, Juan ; Qiao, Liang ; Lan, Hui Y. ; Liu, Xinyuan

OBJECTIVESXIAP-associated factor 1 (XAF1) is a tumor suppressor gene, but its role in angiogenesis is unknown. We investigated whether XAF1 has any antiangiogenesis effect.METHODSMS1 (a mouse endothelial cell line) was infected with an adenoviral vector ZD55-XAF1. Controls were uninfected or infected with ZD55-EGFP. Wound healing assay and tube formation assay were used to assess angiogenesis. Cell proliferation was detected by WST-1 assay, and apoptosis was detected by TUNEL and APOPercentagetrade mark assays.RESULTSZD55-XAF1 significantly upregulated XAF1, which was associated with decreased cell proliferation, migration and tube formation of MS1 cells. Ectopic overexpression of XAF1 induced apoptosis in MS1 and also sensitized cells to 5-fluorouracil-induced apoptosis. A significant decrease in the expression of Tie-1, Ang-1, Ang-2 and c-Myc was observed.CONCLUSIONSOur data suggest that XAF1 possesses a potential antiangiogenesis effect. Suppressed expression of Tie-1, Ang-1, Ang-2 and c-Myc may be mechanistically responsible for the observed antiangiogenesis effect.

2007-01-01·Cancer Gene Therapy2区 · 医学

Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis

2区 · 医学

Article

作者: Z Lin ; B Li ; Z He ; Z Zhang ; X Y Liu ; R Qi ; L Qiao ; C Wang ; K Yang ; J Gu ; J Fan

XAF1 is a newly identified tumor-suppressor gene that can antagonize XIAP and sensitize cells to other cell death triggers. In this study, we utilized ZD55, a conditionally replicative adenovirus (CRAd) similar to ONYX-015 as the vector to transfer XAF1 into the tumor cells to evaluate its antitumor efficacy in vitro and in vivo. Potent and specific cytopathic effect (CPE) was observed upon infection with ZD55-XAF1 in tumor cell lines. Importantly, ZD55-XAF1 exhibited a superior suppression of tumor growth in an animal model of colorectal carcinoma in nude mice compared with Ad-XAF1 (E1-deleted replication-defective viral) and ONYX-015. Complete eradication of the established tumors was observed in four of eight mice. Our data also showed that infection with ZD55-XAF1 resulted in caspase-independent apoptosis. Although caspase-3, poly(ADP-ribose) polymerase were mildly activated in response to ZD55-XAF1 infection, pretreatment with pan-caspase inhibitor hardly influence its apoptosis-inducing activity. In summary, our study strongly suggested that ZD55-XAF1 could serve as an effective gene-virotherapy strategy and has highly potential against human cancers.

100 项与 ZD55-XAF1 相关的药物交易

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