Suicide gene therapy: conversion of ethanol to acetaldehyde mediated by human beta 2 alcohol dehydrogenase.
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 microM, 500 microM 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.
Savage
Philip
P
Cancer Research Wales, Velindre Hospital, Cardiff CF14 2TL, UK. pmsavage@hhnt.nhs.uk
Cowburn
Pam
P
Clemens
Dahn
D
Hurley
Thomas
T
Laguda
Bim
B
Martin-Duque
Pilar
P
Vassaux
Georges
G
Lemoine
Nick R
NR
D000079:Acetaldehyde / Q000378:metabolism / Q000633:toxicity*; D000256:Adenoviridae; D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism*; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000431:Ethanol; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde