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Suicide gene therapy: conversion of ethanol to acetaldehyde mediated by human beta 2 alcohol dehydrogenase

Cancer Gene Therapy volume 11, pages 774–781 (2004)Cite this article

Abstract

Acetaldehyde (AcH) produced in the physiological metabolism of ethanol can be potentially toxic and immunomodulating. The antitumour activity of a suicide gene system using adenovirus delivered alcohol dehydrogenase (ADH) to convert ethanol to acetaldehyde inside cancer cells has been investigated in vitro and in vivo. In vitro experiments confirmed the toxicity of acetaldehyde to a number of tumour cell lines. Daudi lymphoma cells grown in normal media increased by Day 4 to 650% of their starting number, while those exposed to 250 μM, 500 μM and 1 mM acetaldehyde reached 138, 30 and 5% respectively. Adenocarcinoma cells appeared to be less sensitive with CMT-64 cells and HeLa cells numbering 105 and 53% of their starting number by Day 4 with 1 mM acetaldehyde. After transduction with an adenovirus containing the human ADH beta 2 cDNA, CMT-64 cells exposed to 20 mM ethanol had a reduction in number to 74% by Day 2 and to 36% by Day 4. In a preclinical model with Ad-ADH CMT-64 cells, mice exposed to daily pulses of ethanol for 5 days formed tumours only 30% on Day 6 and 42% on Day 13 of the volume of those in mice exposed to water.The ability of this easily administered suicide gene system to produce significant effects on cell proliferation in vivo suggests that further optimized development is warranted.

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Acknowledgements

Thanks to Del Watling, Sandra Peak and colleagues at CRUK Clare Hall for technical support and to the late Leslie Warfield for her support and enthusiasm for this project. This work was supported by a generous donation from the organizers of the Caerphilly Megaday in memory of Andrew Nicholls and Paul Graeme.

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Authors and Affiliations

  1. Cancer Research Wales, Velindre Hospital, Cardiff, CF14 2TL, UK

    Philip Savage & Pam Cowburn

  2. Omaha VAMC, University of Nebraska Medical Center, Research R151, 4101 Woolworth Ave., Omaha, 68105-1850, Nebraska, USA

    Dahn Clemens

  3. Department of Biochemistry and Molecular Biology, Center for Structural Biology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Thomas Hurley

  4. Universidad Francisco de Vitoria, Ctra. Pozuelo-Majadahonda, Km. 1,800, Pozuelo de Alarcon, 28223, Madrid, Spain

    Bim Laguda & Pilar Martin-Duque

  5. Institute of Cancer and CR-UK Clinical Centre, Queen Mary's School of Medicine at Barts & The London, John Vane Science Centre, Charterhouse Square, London, EC1 M 6BQ, UK

    Georges Vassaux & Nick R Lemoine

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  1. Philip Savage
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Correspondence to Philip Savage.

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Savage, P., Cowburn, P., Clemens, D. et al. Suicide gene therapy: conversion of ethanol to acetaldehyde mediated by human beta 2 alcohol dehydrogenase. Cancer Gene Ther 11, 774–781 (2004). https://doi.org/10.1038/sj.cgt.7700764

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