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Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis

Gene Therapy volume 8, pages 369–375 (2001)Cite this article

Abstract

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic effects in vitro and inhibition of tumour growth in vivo of the drug-resistant derivatives, but not the parental line. In apparent contrast, increased apoptosis and reduced clonogenic survival is induced by ONYX-015 infection of the chemosensitive parental cell line. ONYX-015 induces increased pro-apoptotic BAX and reduced anti-apoptotic BCLXL in parental cells, but not in the resistant derivative A2780/cp70. We propose that induction of apoptosis is one factor which prevents ONYX-015 spread and cytolysis after infection of chemosensitive cells, while it is the failure to engage apoptosis in drug-resistant cells that allows preferential viral replication, spread and cytolysis.

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Acknowledgements

We would like to thank Professor SB Kaye, Dr D Stuart and Dr D Kirn for advice and helpful discussion throughout this study and Dr Wilma Steegenga for supplying the Ad5CMVlacZ virus. Onyx Pharmaceuticals supported IG. RB is supported by the Cancer Research Campaign (UK).

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Authors and Affiliations

  1. CRC Department Medical Oncology, CRC Beatson Laboratories, Glasgow, UK

    I Ganly, YT Kim & R Brown

  2. UCSF Cancer Center, San Francisco, CA, USA

    B Hann & A Balmain

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  1. I Ganly
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  2. YT Kim
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Ganly, I., Kim, Y., Hann, B. et al. Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis. Gene Ther 8, 369–375 (2001). https://doi.org/10.1038/sj.gt.3301402

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  • DOI: https://doi.org/10.1038/sj.gt.3301402

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