Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol.
Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5-10 mM paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy.
Tupper
J
J
Tumour Microcirculation Group, Gray Cancer Institute, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, UK.
Tozer
G M
GM
Dachs
G U
GU
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000628:therapy; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods*; D005978:Glutathione / Q000032:analysis; D006735:Horseradish Peroxidase / Q000494:pharmacology*; D006801:Humans; D007097:Imines / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D009303:Nasopharyngeal Neoplasms / Q000628:therapy; D011355:Prodrugs / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D011355:Prodrugs; D000082:Acetaminophen; D006735:Horseradish Peroxidase; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione