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The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

Cancer Gene Therapy volume 14, pages 953–967 (2007)Cite this article

Abstract

Conditionally replicating adenoviruses (CRAd) ‘armed’ with prodrug-activating genes have the potential to augment the efficacy of virotherapy. An Escherichia coli nitroreductase (NTR) gene (nfsB) was introduced into the E3B region of the systemically active CRAd ONYX-411, to produce ONYX-411NTR, which had single agent oncolytic activity equivalent to unarmed virus in vitro and in vivo. A fluorogenic probe (SN 29884) developed to monitor NTR expression revealed robust, durable NTR expression in ONYX-411NTR infected neoplastic but not primary human cell lines. NTR expression occurred >24 h post-infection in parallel with fiber and was sensitive to ara-C indicating transcriptional linkage to viral replication. A novel NTR prodrug, the 3,5-dinitrobenzamide-2-bromomustard SN 27686, was shown to be more dose potent and selective than CB 1954 and provided a superior bystander effect in 3D multicellular layer cultures. Its water-soluble phosphate ester SN 28343 was substantially more active than CB 1954 against xenografts containing a minority of stable NTR-expressing cells. A single intravenous dose of ONYX-411NTR (108 PFU) to nude mice bearing large H1299 xenografts (>350 mm3) resulted in tumor-specific NTR expression which increased over time. Despite extensive viral spread by day 14, this conservative virus dose and schedule was unable to control such well-established tumors. However, subsequent administration of SN 28343 resulted in the majority of mice (62.5%) being tumor-free on day 120.

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Acknowledgements

We thank Yongchuan Gu for assistance with the pharmacokinetic study, Alison Hogg and Chenbo Wu, for technical assistance with growth delay studies, Dr Shangjin Yang and Graham Atwell for synthesis of CB 1954, SN 27686 and SN 28343 and Dr Leonard Post (Onyx Pharmaceuticals Inc.) for helpful council. This study was funded by grant 01/027 from the Health Research Council of New Zealand.

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  1. Y Shen

    Present address: 3Current address: Applied Biomics Inc., Hayward, CA 94545, USA,

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  1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    D C Singleton, D Li, S Y Bai, S P Syddall, J B Smaill, W A Denny, W R Wilson & A V Patterson

  2. Onyx Pharmaceuticals Inc., Emeryville, CA, USA

    Y Shen

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Singleton, D., Li, D., Bai, S. et al. The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR. Cancer Gene Ther 14, 953–967 (2007). https://doi.org/10.1038/sj.cgt.7701088

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