Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL.
Chemoresistance and side effects are considered as the major obstacles in cisplatin-based chemotherapy of various human malignant tumors. Conjugation with cancer-specific apoptotic stimuli TRAIL or typical viro-agent ONYX-015 has been extensively investigated to enhance the antitumor activity of cisplatin. In this study, we presented a novel chemo-gene-virotherapeutic strategy to further improve the toxic effects in cancer cells and reduce the damage in normal cells. Here, an oncolytic adenoviral vector (ZD55), with a deletion of E1B 55-kDa gene, was employed to express the therapeutic TRAIL gene by constructing a recombinant virus ZD55-TRAIL. Exogenous gene delivery efficacy was determined by both in vitro and in vivo experiments and enhanced cytotoxicity of combined treatment of ZD55-TRAIL with cisplatin was evaluated in several cancer cell lines. Moreover, negative effects on normal cells have been tested in both L-02 and MRC-5 cell lines by MTT assay and apoptotic cell staining. According to our observation, combination of ZD55-TRAIL with cisplatin exhibited an apparent synergistic cytotoxicity in cancer cells, yet significantly abolished the negative toxicity in normal cells by reducing the dosage. Thus, a novel chemo-gene-virotherapeutic strategy for cancer therapy was proposed.
Pan
Qiuwei
Q
Xin Yuan Institute of Medicine and Biotechnology, Life Science College, Zhejiang Sci-Tech University, Hangzhou 310018, China.
Liu
Bisheng
B
Liu
Jin
J
Cai
Rong
R
Wang
Yigang
Y
Qian
Cheng
C
D000256:Adenoviridae / Q000187:drug effects / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014765:Viral Vaccines
D053221:TNF-Related Apoptosis-Inducing Ligand; D014765:Viral Vaccines; C464532:dl1520; D002945:Cisplatin