Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24

• Published in: Acta pharmacologica Sinica Vol. 30; no. 4; pp. 467 - 477
• Main Authors: Wu, Yu-mei, Zhang, Kang-jian, Yue, Xue-tian, Wang, Yi-qiang, Yang, Yi, Li, Gong-chu, Li, Na, Wang, Yi-gang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2009; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Antineoplastic Agents - pharmacology; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell death; Cell Line; Cisplatin - pharmacology; Combined Modality Therapy; Dose-Response Relationship, Drug; Genetic Therapy; Humans; Immunology; Interleukins - genetics; Internal Medicine; MDA-7/IL-24; Medical Microbiology; Neoplasms - pathology; Neoplasms - therapy; Oncolytic Virotherapy; Original; original-article; Pharmacology/Toxicology; Vaccine; 流式细胞仪分析; 溶瘤腺病毒; 白细胞介素24; 肿瘤细胞死亡; 腺病毒携带; 诱导凋亡作用; apoptosis; MDA-7/IL-24; oncolytic adenovirus; cisplatin
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/aps.2009.16

Aim： The aim of this study was to creatively implement a novel chemo-gene-virotherapeutic strategy and further strengthen the antitumor effect in cancer cells by the combined use of ZD55-IL-24 and cisplafin. Methods： ZD55-IL-24 is an oncolytic adenovirus that harbors interleukin 24 （IL-24）, which has a strong antitumor effect and was identified and evaluated by PCR, RT-PCR, and Western blot analysis. Enhancement of cancer cell death using a combination of ZD55-IL-24 and cisplatin was assessed in several cancer cell lines by the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay and cytopathic effect （CPE） assay. Apoptosis induction by treatment with ZD55-IL-24 and/or cisplatin was detected in BEL7404 and SMMC7721 by morphological evaluation, apoptotic cell staining, and flow cytometry analysis. In addition, negative effects on normal cells were evaluated in the L-02 cell line using the MTT assay, the CPE assay, morphological evaluation, apoptotic cell staining, and flow cytometry analysis. Results： The combination of ZD55-IL-24 and cisplatin, which is superior to ZD55-IL-24, cisplatin, and ZD55-EGFP, as well as ZD55-EGFP plus cisplatin, resulted in a significantly increased effect. Most importantly, conjugation of ZD55-IL-24 with cisplatin had toxic effects equal to that of cisplatin and did not have overlapping toxicities in normal cells. Conclusions： This study showed that ZD55-IL-24 conjugated with cisplatin exhibited a remarkably increased cytotoxic and apoptosis-inducing effect in cancer cells and significantly reduced the toxicity in normal cells through the use of a reduced dose.