Oncotarget

Research Papers:

Selective elimination of long INterspersed element-1 expressing tumour cells by targeted expression of the HSV-TK suicide gene

Mariam Chendeb _, Robert Schneider, Irwin Davidson and Anas Fadloun

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Oncotarget. 2017; 8:38239-38250. https://doi.org/10.18632/oncotarget.16013

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Abstract

Mariam Chendeb1, Robert Schneider1,2, Irwin Davidson1,3 and Anas Fadloun2

1 Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, Cédex, France

2 Institute of Functional Epigenetics, Helmholtz Center Munich, Neuherberg, Germany

3 Equipe Labellisée of the Ligue Nationale Contre le Cancer, Corvisart, Paris, France

Correspondence to:

Anas Fadloun, email:

Irwin Davidson, email:

Keywords: L1 retrotransposon, Alu element, HSV-TK suicide gene, genome integration, cancer therapy

Received: January 14, 2017 Accepted: March 02, 2017 Published: March 08, 2017

Abstract

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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