Thiram inhibits angiogenesis and slows the development of experimental tumours in mice.
Thiram-tetramethylthiuram disulphide--a chelator of heavy metals, inhibited DNA synthesis and induced apoptosis in cultured bovine capillary endothelial cells. Bovine capillary endothelial cells were 10-60-fold more sensitive to thiram than other cell types. These effects were prevented by addition of antioxidants, indicating involvement of reactive oxygen species. Exogenously added Cu2+ impeded specifically and almost completely the inhibitory effect of thiram for bovine capillary endothelial cells. Moreover, thiram had markedly inhibited human recombinant Cu/Zn superoxide dismutase enzymatic activity (85%) in vitro. Moreover, PC12-SOD cells with elevated Cu/Zn superoxide dismutase were less sensitive to thiram treatment than control cells. These data indicate that the effects of thiram are mediated by inhibition of Cu/Zn superoxide dismutase activity. Oral administration of thiram (13-30 microg mouse(-1)), inhibited angiogenesis in CD1 nude mice. Tumour development is known to largely depend on angiogenesis. We found that oral administration of thiram (30 microg) to mice caused significant inhibition of C6 glioma tumour development (60%) and marked reduction (by 3-5-fold) in metastatic growth of Lewis lung carcinoma. The data establish thiram as a potential inhibitor of angiogenesis and raise the possibility for its use as therapy in pathologies in which neovascularisation is involved, including neoplasia.
Marikovsky
M
M
Department of Animal Sciences, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot 76100, Israel. marikovs@agri.huji.ac.il
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology* / Q000662:veterinary; D018827:Carcinoma, Lewis Lung / Q000473:pathology*; D002417:Cattle; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology* / Q000662:veterinary; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013893:Thiram / Q000494:pharmacology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D013893:Thiram; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1