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The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

Gene Therapy volume 18, pages 1157–1165 (2011)Cite this article

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Abstract

Pancreatic adenocarcinomas are aggressive and frequently develop resistance to all current therapies. Replication-selective adenoviruses can overcome resistance to chemotherapeutics through their sensitizing effects on drug-induced cell killing. We previously found that adenovirus deleted in the anti-apoptotic E1B19K gene enhanced gemcitabine-induced apoptotis. Here we demonstrate that our engineered double-deleted AdΔΔ mutant (deleted in the pRb-binding E1ACR2 region and E1B19K) selectively replicates and enhances cell killing in combination with DNA-damaging cytotoxic drugs in pancreatic cancer cells. Combinations of AdΔΔ with gemcitabine, irinotecan or cisplatin resulted in two- to fourfold decreases in EC50 (half maximal effective concentration) values and was more efficent than similar combinations with wild-type virus, the dl1520 (ONYX-015) and dl922-947 mutants. AdΔΔ replication was impaired in normal bronchial human epithelial cells and did not sensitize the cells to drugs. Gemcitabine-insensitive AsPC-1, BxPC-3 and PANC-1 cells were efficiently killed by irinotecan in combination with AdΔΔ. Suboptimal doses of AdΔΔ and gemcitabine significantly prolonged time to tumor progression in two human pancreatic tumor xenograft in vivo models, PT45 and SUIT-2. We conclude that AdΔΔ has low toxicity to normal cells while potently sensitizing pancreatic cancer cells to DNA-damaging drugs, and holds promise as an improved therapeutic strategy for pancreatic cancer.

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Acknowledgements

We thank Gary Martin and colleagues at Clare Hall (Cancer Research UK) for excellent experimental assistance; Keyur Trivedi and Mohammed Ikram (Centre for Molecular Oncology and Imaging, Barts Cancer Institute) for immunohistochemistry; Derek Davies (Cancer research UK) for cell cycle expertize; Daniel Öberg (Centre for Molecular Oncology and Imaging) and Ian Hart for insightful discussions (Tumour Biology, Barts Cancer Institute). This study was supported by grants from the CORE Digestive Cancer Campaign, Cancer Research UK (C633-A6253/A6251 programme grant) and Barts & The London Charity.

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Authors and Affiliations

  1. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

    G Cherubini, A Mozetic, H Müller, N R Lemoine & G Halldén

  2. The Royal Veterinary College, Hawkshead Lane, Hatfield, UK

    C Kallin & K Hammaren-Busch

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  1. G Cherubini
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Correspondence to G Halldén.

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Cherubini, G., Kallin, C., Mozetic, A. et al. The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models. Gene Ther 18, 1157–1165 (2011). https://doi.org/10.1038/gt.2011.141

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