Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase.
Reactivation of telomerase maintains telomere function and is considered critical to immortalization in most human cancer cells. Elevation of telomerase expression in cancer cells is highly specific: transcription of both RNA (hTR) and protein (hTERT) components is strongly upregulated in cancer cells relative to normal cells. Therefore, telomerase promoters may be useful in cancer gene therapy by selectively expressing suicide genes in cancer cells and not normal cells. One example of suicide gene therapy is the bacterial nitroreductase (NTR) gene, which bioactivates the prodrug CB1954 into an active cytotoxic alkylating agent. We describe construction of adenovirus vectors harbouring the bacterial NTR gene under control of the hTR or hTERT promoters. Western blot analysis of NTR expression in normal and cancer cells infected with adenoviral vectors showed cancer cell-specific nitroreductase expression. Infection with adenoviral telomerase-NTR constructs in a panel of seven cancer cell lines resulted in up to 18-fold sensitization to the prodrug CB1954, an effect that was retained in two drug-resistant ovarian lines. Importantly, no sensitization was observed with either promoter in any of the four normal cell strains. Finally, an efficacious effect was observed in cervical and ovarian xenograft models following single intratumoural injection with low doses of vector, followed by injection with CB1954.
Bilsland
Alan E
AE
Cancer Research UK Department of Medical Oncology, University of Glascow, Cancer Research UK Beatson Laboratories, Bearsden, UK.
Anderson
Claire J
CJ
Fletcher-Monaghan
Aileen J
AJ
McGregor
Fiona
F
Evans
T R Jeffry
TR
Ganly
Ian
I
Knox
Richard J
RJ
Plumb
Jane A
JA
Keith
W Nicol
WN
D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001388:Aziridines / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009601:Nitroreductases / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000628:therapy
D000970:Antineoplastic Agents; D001388:Aziridines; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C100099:tretazicar; D009601:Nitroreductases; D019098:Telomerase