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Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs

Cancer Gene Therapy volume 18, pages 724–733 (2011)Cite this article

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Abstract

Although previous studies modified two components of conditionally replicating adenoviruses (CRAs), which selectively replicate in and kill cancer cells, the most accurate ways to achieve increased cancer specificity (that is, safety) without reducing the anticancer (that is, therapeutic) effects are unknown. Here, we generated two types of survivin-responsive m-CRAs (Surv.m-CRAs), Surv.m-CRA-CMVp and Surv.m-CRA-OCp, which use two and three different mechanisms to target cancer, that is, early region 1A (E1A) regulated by the survivin promoter and mutated E1BΔ55K regulated by the ubiquitously active cytomegalovirus promoter and cancer/tissue-specific osteocalcin promoter, respectively, and carefully examined their safety and anticancer effects. Endogenous osteocalcin mRNA was expressed and further enhanced by vitamin D3 in all osteosarcoma and prostate cancer cell lines and human osteoblasts, but not in human fibroblasts. The osteocalcin promoter activity was weak even with vitamin D3 treatment in these osteocalcin-expressing cancers, leading to low E1BΔ55K expression after Surv.m-CRA-OCp infection. Nevertheless, Surv.m-CRA-OCp had significantly increased cancer specificity without reduced anticancer effects in both in vitro and in vivo experiments. The unexpected but favorable fact that strong activity of an altered E1B promoter is unnecessary indicates that the majority of cancer/tissue-specific promoters may be used to generate ideal m-CRAs and will advance the development of m-CRA-based cancer therapies.

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Acknowledgements

We thank S Yamashita for technical assistance. This work was supported by a grant for Promoting Business using Advanced Technology from the Japan Society and Technology Agency, and Health and Labor Science Research Grants for Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan.

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Authors and Affiliations

  1. Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Y Horikawa, Y Wang, M Ikeda & K-i Kosai

  2. Department of Orthopaedic Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Y Horikawa, S Nagano, J Kamizono & S Komiya

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  1. Y Horikawa
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  2. Y Wang
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  3. S Nagano
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Correspondence to K-i Kosai.

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K Kosai is the founder of WyK BiotechPharma Inc., but does not earn a salary from the company. No other potential conflict of interest was disclosed.

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Horikawa, Y., Wang, Y., Nagano, S. et al. Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs. Cancer Gene Ther 18, 724–733 (2011). https://doi.org/10.1038/cgt.2011.44

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