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Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene.
Oncotarget 8, 38239-38250 (2017)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Alu Element ; Hsv-tk Suicide Gene ; L1 Retrotransposon ; Cancer Therapy ; Genome Integration; Somatic L1 Retrotransposition; Alu Repeats; Line-1 Retrotransposition; Cultured-cells; Human-disease; Cancer; Carcinoma; Therapy; Insertions; Evolution
ISSN (print) / ISBN
1949-2553
e-ISSN
1949-2553
Journal
OncoTarget
Quellenangaben
Volume: 8,
Issue: 24,
Pages: 38239-38250
Publisher
Impact Journals LLC
Publishing Place
Orchard Park
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Functional Epigenetics (IFE)