Development of a novel enzyme/prodrug combination for gene therapy of cancer: horseradish peroxidase/indole-3-acetic acid.
This paper demonstrates the potential for utilizing the plant enzyme, horseradish peroxidase (HRP), in a gene-directed enzyme prodrug therapy context. Human T24 bladder carcinoma cells transfected with a mammalian expression vector containing the HRP cDNA were selectively sensitized to the nontoxic plant hormone, indole-3-acetic acid (IAA). The HRP/IAA-induced cell kill was effective in normoxic and anoxic conditions. The activated drug is a long-lived species able to cross cell membranes, and cell contact appears not to be required for a bystander effect to take place. These preliminary results suggest that the delivery of the HRP gene to human tumors followed by IAA treatment may provide a novel cancer gene-directed enzyme prodrug therapy approach, with potential to target hypoxic cells.
Greco
O
O
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Folkes
L K
LK
Wardman
P
P
Tozer
G M
GM
Dachs
G U
GU
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057487:Enzyme Therapy; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy / Q000379:methods*; D006735:Horseradish Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D007210:Indoleacetic Acids / Q000378:metabolism* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009369:Neoplasms / Q000628:therapy*; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011355:Prodrugs; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D007210:Indoleacetic Acids; D011355:Prodrugs; C030737:indoleacetic acid; D006735:Horseradish Peroxidase; D010100:Oxygen