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Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer

Cancer Gene Therapy volume 19, pages 320–327 (2012)Cite this article

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Abstract

Activity and specificity of chemotherapeutic agents against solid tumors can be augmented via the targeted or localized delivery of ‘suicide’ genes. Selective activation of specific prodrugs in cells expressing the ‘suicide’ gene drives their elimination by apoptosis, while also enabling the killing of adjacent bystander cells. Strong bystander effects can compensate for poor ‘suicide’ gene delivery, and depend on the prodrugs used and mechanisms for the acquisition of activated drug by the bystander population, such as the presence of gap junctional intercellular communications. Although a number of ‘suicide’ gene therapies for cancer have been developed and characterized, such as herpes simplex virus-derived thymidine kinase (HSV-tk)-based activation of ganciclovir, their limited success highlights the need for the development of more robust approaches. Limiting activation kinetics and evolution of chemoresistance are major obstacles. Here we describe ‘suicide’ gene therapy of cancer based on the lentivirus-mediated delivery of a thymidine-active human deoxycytidine kinase variant. This enzyme possesses substrate plasticity that enables it to activate a multitude of prodrugs, some with distinct mechanisms of action. We evaluated the magnitude and mechanisms of bystander effects induced by different prodrugs, and show that when used in combination, they can synergistically enhance the bystander effect while avoiding off-target toxicity.

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Acknowledgements

We would like to acknowledge Dr Jeff C Liu, Dr Giovanni Ciavarra and Dr Eldad Zacksenhaus (Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON) for their assistance with fluorescent microscopy. Funding for AN was provided by the CIHR Training Program in Regenerative Medicine (TPRM). This research was funded in part by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC.

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Authors and Affiliations

  1. Department of Medical Biophysics, University Health Network,

    A Neschadim & J A Medin

  2. University of Toronto, Toronto, Ontario, Canada

    A Neschadim & J A Medin

  3. Institute of Medical Science, Toronto, Ontario, Canada

    J C M Wang & J A Medin

  4. Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

    A Lavie

  5. University Health Network, Toronto, Ontario, Canada

    J A Medin

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Correspondence to J A Medin.

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Neschadim, A., Wang, J., Lavie, A. et al. Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer. Cancer Gene Ther 19, 320–327 (2012). https://doi.org/10.1038/cgt.2012.4

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