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Enhanced Sensitivity of Lymphoid Cells to Ethanol ADH Acetaldehyde Toxicity; Implications for GDEPT and Adoptive T Cell Therapy

[ Vol. 16 , Issue. 2 ]

Author(s):

Philip Savage*, Claire Horlock, Bryony Stott and Justin Stebbing   Pages 118 - 123 ( 6 )

Abstract:


Background: The ability to kill lymphoid cells with a non-toxic prodrug/gene/ toxin system would be of value in the treatment of lymphoid malignancies and in the regulation of T cells used in adoptive immunotherapy.

Objective: In this in vitro study we examined the ability of a novel prodrug/gene/toxin system to produce cytotoxicity in lymphoid cells. The system uses a non-toxic prodrug ethanol, human alcohol dehydrogenase and exerts the toxic action via the prolonged production of acetaldehyde produced within targeted cells.

Methods: Raji B cells were transduced with an alcohol dehydrogenase containing lentivirus and then exposed to differing durations of daily ethanol exposure. Cell numbers and viability were assessed by trypan blue exclusion.

Results: Individually, ethanol and the ADH gene were non-toxic to Raji B cells. Exposure of ADH transduced cells to ethanol produced prompt growth inhibition and later cell killing that could be negated by the presence of 4-MP the alcohol dehydrogenase inhibitor. At 96 hours exposure to ethanol the number of ADH transduced cells had declined by up to 66% and their total number comprised only 2% of the proliferating untreated control cells.

Conclusion: The ethanol ADH acetaldehyde system offers a simple, safe, non-toxic approach to cancer therapy prodrug toxin technology. It may also offer a safe and non-toxic system to control the number and action of T cells used in adoptive immunotherapy.

Keywords:

G-DEPT, cancer, gene therapy, ethanol, acetaldehyde, T cells.

Affiliation:

Department of Medical Oncology, Imperial Hospitals NHS Trust, London, Department of Medical Oncology, Imperial Hospitals NHS Trust, London, Department of Medical Oncology, Imperial Hospitals NHS Trust, London, Department of Medical Oncology, Imperial Hospitals NHS Trust, London

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