1. ¹Cancer Research Wales, Velindre Hospital, Cardiff CF14 2TL, UK
2. ²Omaha VAMC, University of Nebraska Medical Center, Research R151, 4101 Woolworth Ave., Omaha, Nebraska 68105-1850, USA
3. ³Center for Structural Biology, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
4. ⁴Universidad Francisco de Vitoria, Ctra. Pozuelo-Majadahonda, Km. 1,800. 28223 Pozuelo de Alarcon, Madrid, Spain
5. ⁵Institute 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

Correspondence: Dr Philip Savage, Department of Medical Oncology, Charing Cross Hospital, London, UK W6 8RF. E-mail: pmsavage@hhnt.nhs.uk

Received 17 March 2004; Published online 22 October 2004.

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 M, 500 M 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.