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Potent Antitumor Efficacy of XAF1 Delivered by Conditionally Replicative Adenovirus Vector via Caspase-Independent Apoptosis

Author: QiRong
Tutor: LinZhiXin;LiuXinYuan
School: Shanghai Jiaotong University
Course: Biochemistry and Molecular Biology
Keywords: Oncolytic adenovirus Gene - the virus treatment ONYX-015 ZD55 XAF1 Does not depend on the apoptosis of caspase
CLC: R730.5
Type: PhD thesis
Year: 2008
Downloads: 143
Quote: 0
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Abstract


Conditionally replicative adenovirus (CRAd) is a potential therapeutic adenovirus for cancer because it can selectively replicate in tumor cells and kill them, but not in normal cells. One strategy to construct CRAd is to to delete gene functions that are necessary for efficient viral replication in normal cells, but not in tumor cells. ONYX-015 is one such genetically engineered CRAd, which can selectively replicate in p53 pathway-dysfunctional tumor cells by deletion of E1B55kD gene. Over 200 cancer patients have been treated to date on over 10 clinical trials (phases I-III).However, it is of note that ONYX-015 is safe but not potent enough as a monotherapy to cause complete tumor regression or generate sustained clinical responses. To address this problem, our group put forward a novel concept of Targeting Gene-ViroTherapy strategy and in this way, we constructed an armed therapeutic CRAd system, ZD55-gene, which is not only deleted of E1B55kD gene similar to ONYX-015, but also armed with foreign antitumor gene. ZD55-gene exhibited similar cytopathic effects and replication kinetics to that of ONYX-015 in vitro. Importantly, the carried gene is expressed and the expression level can be increased with the replication of virus.XAF1 (XIAP-associated factor 1) was first isolated by the yeast two-hybrid technique on the basis of its ability to bind XIAP via the zinc-finger region. It was reported to directly antagonize the anti-caspase activity of XIAP or trigger a nuclear translocation of XIAP. XAF1 is widely expressed in most normal tissues, but in cancer tissues, its expression is very low or undetectable. Recently, it was demonstrated that CpG dinucleotides upstream of the XAF1 start codon were differentially methylated in human gastric and colonic tumors, further implicating that XAF1 acts as a tumor suppressor gene. Over-expression of XAF1 doesn’t appear to induce apoptosis, while previous studies have shown that over-expression of XAF1 could sensitize cancer cells to the pro-apoptotic effects of etoposide and TRAIL. Recently it was reported that XAF1 can co-operate with TNFαin the induction of apoptosis. These studies suggest that combining XAF1 with other cell death triggers might make a preferable choice for gene therapy. 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.Firstly, ZD55 is an efficient gene delivery vector. ZD55 can replicate and spread throughout the tumor tissue, thereby delivers a high dose of a therapeutic gene product efficiently and selectively to tumor cells. Insertion of XAF1 did not attenuate the replication ability of the virus. Potent and specific cytopathic effect (CPE) was observed upon infection with ZD55-XAF1 in tumor cell lines even at very low MOI (MOI=0.1).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, PARP were mildly activated in response to ZD55-XAF1 infection, pretreatment with pan-caspase inhibitor hardly influence its apoptosis-inducing activity. Inconsistent with previous report, we found that over-expression couldn’t sequester XIAP from cytoplasm to nucleus.In summary, our study strongly suggested that ZD55-XAF1 could serve as an effective gene-virotherapy strategy and has highly potential against human cancers.

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CLC: > Medicine, health > Oncology > General issues > Tumor Therapy
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