In vivo characterization of horseradish peroxidase with indole-3-acetic acid and 5-bromoindole-3-acetic acid for gene therapy of cancer.
Gene-directed enzyme prodrug therapy is a form of targeted cancer therapy, in which an enzyme is used to convert a non-toxic prodrug to a cytotoxin within the tumor. Horseradish peroxidase (HRP) is able to convert the indole prodrugs indole-3-acetic acid (IAA) and the halogenated derivative 5-bromo-IAA (5Br-IAA) to toxic agents able to induce cell kill in vitro. This study characterized HRP-directed gene therapy in vivo. Human nasopharyngeal squamous cell carcinoma cells, FaDu, stably expressing HRP were grown as xenografts in SCID mice. Pharmacokinetic analysis of IAA and 5Br-IAA showed satisfactory drug profiles, and millimolar concentrations could be achieved in tumor tissue at non-toxic doses. HRP-expressing tumors showed a modest growth delay when treated with IAA compared with drug-vehicle controls. Treatment response could not be improved using different drug scheduling or drug vehicle, nor by combining HRP-directed gene therapy with fractionated radiotherapy.
Tupper
J
J
Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK.
Stratford
M R
MR
Hill
S
S
Tozer
G M
GM
Dachs
G U
GU
D000818:Animals; D019540:Area Under Curve; D001966:Bromine / Q000737:chemistry; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods; D019076:Transgenes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D007210:Indoleacetic Acids; D011355:Prodrugs; D049452:Green Fluorescent Proteins; C030737:indoleacetic acid; D006735:Horseradish Peroxidase; D001966:Bromine