Oxidative activation of indole-3-acetic acids to cytotoxic species- a potential new role for plant auxins in cancer therapy.
Indole-3-acetic acid (IAA) and some derivatives can be oxidised by horseradish peroxidase (HRP) to cytotoxic species. Upon treatment with IAA/HRP, liposomes undergo lipid peroxidation, strand breaks and adducts are formed in supercoiled plasmid DNA, and mammalian cells in culture lose colony-forming ability. IAA is only toxic after oxidative decarboxylation; no effects are seen when IAA or HRP is incubated independently in these systems at equivalent concentrations. Toxicity is similar in both hamster fibroblasts and some human tumour cells. The effect of IAA/HRP is thought to be due in part to the formation of 3-methylene-2-oxindole, which may conjugate with DNA bases and protein thiols. Our hypothesis is that IAA/HRP could be used as the basis for targeted cancer therapy involving antibody-, polymer-, or gene-directed approaches. HRP can thus be targeted to a tumour allowing non-toxic IAA delivered systemically to be activated only in the tumour. Exposure to newly synthesised analogues of IAA shows a range of four orders of magnitude difference in cellular toxicity but no structure-activity relationships are apparent, in contrast to well-defined redox dependencies of oxidation by HRP intermediates or rates of decarboxylation of radical-cation intermediates.
Folkes
L K
LK
Gray Laboratory Cancer Research Trust, PO Box 100, Mount Vernon Hospital, Northwood, HA6 2JR, Middlesex, UK. folkes@graylab.ac.uk
Wardman
P
P
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006735:Horseradish Peroxidase / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007210:Indoleacetic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D007210:Indoleacetic Acids; D011355:Prodrugs; C030737:indoleacetic acid; D006735:Horseradish Peroxidase