Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene.
Fiche publication
Date publication
mars 2017
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIDSON Irwin
Tous les auteurs :
Chendeb M, Schneider R, Davidson I, Fadloun A
Lien Pubmed
Résumé
In gene therapy, effective and selective suicide gene expression is crucial. We exploited the endogenous Long INterspersed Element-1 (L1) machinery often reactivated in human cancers to integrate the Herpes Simplex Virus Thymidine Kinase (HSV-TK) suicide gene selectively into the genome of cancer cells. We developed a plasmid-based system directing HSV-TK expression only when reverse transcribed and integrated in the host genome via the endogenous L1 ORF1/2 proteins and an Alu element. Delivery of these new constructs into cells followed by Ganciclovir (GCV) treatment selectively induced mortality of L1 ORF1/2 protein expressing cancer cells, but had no effect on primary cells that do not express L1 ORF1/2. This novel strategy for selective targeting of tumour cells provides high tolerability as the HSV-TK gene cannot be expressed without reverse transcription and integration, and high selectivity as these processes take place only in cancer cells expressing high levels of functional L1 ORF1/2.
Mots clés
Alu element, HSV-TK suicide gene, L1 retrotransposon, cancer therapy, genome integration
Référence
Oncotarget. 2017 Mar;: