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Current Pharmacogenomics and Personalized Medicine

Editor-in-Chief

ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Research Article

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

Author(s): Philip Savage*, Claire Horlock, Bryony Stott and Justin Stebbing

Volume 16, Issue 2, 2018

Page: [118 - 123] Pages: 6

DOI: 10.2174/1875692116666180703151538

Price: $65

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.

Graphical Abstract

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