Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases

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

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.sTβRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTβRFc expressing soluble transforming growth factor beta receptorII-Fc fusion protein (sTGβRIIFc), were replaced by those of Ad48. mHAd.sTβRFc, like Ad.sTβRFc, was replication competent in the human PCa cells, and produced high levels of sTGβRIIFc expression. Compared to Ad.sTβRFc, the systemic delivery of mHAd.sTβRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTβRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTβRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTβRFc or mHAd.sTβRFc (5 × 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.sTβRFc (4 × 10 11 viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTβRFc could be developed for the treatment of PCa bone metastases.

Original languageEnglish (US)
Pages (from-to)1504-1517
Number of pages14
JournalMolecular Therapy
Volume22
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Xu, W., Zhang, Z., Yang, Y., Hu, Z., Wang, C. H., Morgan, M., Wu, Y., Hutten, R., Xiao, X., Stock, S., Guise, T., Prabhakar, B. S., Brendler, C., & Seth, P. (2014). Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases. Molecular Therapy, 22(8), 1504-1517. https://doi.org/10.1038/mt.2014.80