Suicide gene therapy for premalignant disease: a new strategy for the treatment of intraepithelial neoplasia

Gene Therapy
Z SandalonJ A Garlick

Abstract

The potential of gene therapy to treat premalignant disease or recurrent cancer has not been investigated. The goal of the present investigation was to explore the efficacy of pro-drug-mediated, suicide gene therapy as a strategy to treat incipient neoplasia in stratified squamous epithelium. To test this strategy, a tissue model of premalignancy was generated by mixing normal human keratinocytes (NHK) that express the bacterial cytosine deaminase gene (CD) with premalignant keratinocytes which have been genetically marked with the bacterial gene for beta-galactosidase (II-4-beta-gal) in skin-like organotypic cultures. Preliminary studies in monolayer cultures demonstrated that CD-transduced NHK (NHK/CD) efficiently expressed the transgene and deaminated the pro-drug 5-fluorocytosine (5FC) to the toxic product 5-fluorouracil (5FU). The capacity of NHK/CD to kill II-4-beta-gal cells through bystander effect was assayed in both submerged culture and in the organotypic model of premalignancy. In submerged cultures, it was found that CD-mediated killing of II-4-beta-gal cells did not require cell-cell contact and that the LD(50) of 5FC for efficient bystander killing of II-4-beta-gal was 0.5 mM. When this concentration of pro-drug ...Continue Reading

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Citations

Jul 20, 2002·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·John Nemunaitis, Casey Cunningham
Mar 14, 2002·Expert Opinion on Biological Therapy·John Nemunaitis, John O'Brien
May 20, 2008·The Journal of Pathology·K GaballahM Partridge
Sep 10, 2005·International Journal of Cancer. Journal International Du Cancer·Alexander MargulisJonathan A Garlick
Oct 26, 2005·Journal of Assisted Reproduction and Genetics·Georgia S TzamaloukaJoannes El Chliaoutakis
Jul 29, 2011·Journal of Cellular and Molecular Medicine·Xin-Ran LiuXin-Yuan Liu

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