Ad5/48 Hexon Oncolytic Virus Expressing sTGF beta RIIFc Produces Reduced Hepatic and Systemic Toxicities and Inhibits Prostate Cancer Bone Metastases

作者：Xu Weidong; Zhang Zhenwei; Yang Yuefeng; Hu Zebin; Wang Chi Hsiung; Morgan Melanie; Wu Ying; Hutten Ryan; Xiao Xianghui; Stock Stuart; Guise Theresa; Prabhakar Bellur S; Brendler Charles; Seth Prem^*

来源：Molecular Therapy, 2014, 22(8): 1504-1517.

DOI：10.1038/mt.2014.80

We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sT beta RFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sT beta RFc expressing soluble transforming growth factor beta receptorll-Fc fusion protein (sTG beta RIIFc), were replaced by those of Ad48. mHAd.sT beta RFc, like Ad.sT beta RFc, was replication competent in the human PCa cells, and produced high levels of sTG beta RIIFc expression. Compared to Ad.sT beta RFc, the systemic delivery of mHAd.sT beta RFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sT beta RFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-alpha, and interleukin-6 levels, while mHAd.sT beta RFc produced much reduced responses of these markers. Intravenous delivery of Ad.sT beta RFc or mHAd.sT beta RFc (5 x 10(10) viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sT beta RFc (4 x 10(11) viral particles/mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sT beta RFc could be developed for the treatment of PCa bone metastases.

• 出版日期2014-8
• 单位西北大学