Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954.
A recombinant retrovirus encoding E. coli nitroreductase (NTR) was used to infect mammalian cells. NIH3T3 cells expressing NTR were killed by the prodrug CB1954, which NTR converts to a bifunctional alkylating agent. Admixed, unmodified NIH3T3 cells could also be killed. In contrast to the Herpes simplex virus (HSV) thymidine kinase (TK)/ganciclovir(GCV) enzyme/prodrug system, NTR/CB1954 cell killing was effective in non-cycling cells. Co-operative killing was observed when cells expressing both NTR and TK were treated with a combination of CB1954 and GCV. NTR expression in human melanoma, ovarian carcinoma or mesothelioma cells also rendered them sensitive to CB1954 killing. These data suggest that delivery of the NTR gene to human tumours, followed by treatment with CB1954, may provide a novel tumour gene therapy approach.
Bridgewater
J A
JA
CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London, UK.
Springer
C J
CJ
Knox
R J
RJ
Minton
N P
NP
Michael
N P
NP
Collins
M K
MK
D016475:3T3 Cells / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005798:Genes, Bacterial; D005814:Genes, Viral; D006801:Humans; D051379:Mice; D009601:Nitroreductases / Q000235:genetics* / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000235:genetics / Q000627:therapeutic use; D015678:Viral Structural Proteins / Q000235:genetics
D001388:Aziridines; D011355:Prodrugs; D015678:Viral Structural Proteins; C100099:tretazicar; D009601:Nitroreductases; D013937:Thymidine Kinase; D015774:Ganciclovir