Genotoxicity of streptozotocin in normal and cancer cells and its modulation by free radical scavengers.
Streptozotocin (STZ) is an antibiotic which can be used to induce diabetes in experimental animals in order to have an insight into pathogenesis of this disease. To use STZ as a diabetogenic substance, its molecular mode of action should be elucidated. Using the alkaline comet assay, we showed that STZ at concentrations in the range 0.01-100 micromol/L induced DNA damage in normal human lymphocytes and HeLa cancer cells in a dose-dependent manner. Lymphocytes were able to remove damage to their DNA within a 30-min repair incubation, whereas HeLa cells completed the repair in 60 min. Vitamins C and E at 10 and 50 micromol/L diminished the extent of DNA damage induced by 50 micromol/L STZ. Pretreatment of the lymphocytes with the nitrone spin trap, alpha-(4-pyridil-1-oxide)-N-tert-butylnitrone (POBN) or ebselen, which mimics glutathione peroxidase, or pyrrolidine dithiocarbamate (PDTC) reduced the extent of DNA damage evoked by STZ. The cells exposed to STZ and treated with endonuclease III (Endo III), formamidopyrimidine-DNA glycosylase (Fpg) and 3-methyladenine-DNA glycosylase II (AlkA), the enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes. These results suggest that free radicals may be involved in the formation of DNA lesions induced by streptozotocin. The drug can also alkylate DNA bases. This broad range of DNA damage induced by STZ indicates that the drug may seriously affect genomic stability in normal and pathological cells.
Błasiak
J
J
Department of Molecular Genetics, University of Lodz, Lodz, Poland. januszb@biol.uni.lodz.pl
Sikora
A
A
Wozniak
K
K
Drzewoski
J
J
D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001205:Ascorbic Acid / Q000494:pharmacology; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D009153:Mutagens / Q000633:toxicity*; D009589:Nitrogen Oxides / Q000494:pharmacology; D011725:Pyridines; D013311:Streptozocin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D014810:Vitamin E / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D016166:Free Radical Scavengers; D009153:Mutagens; D009589:Nitrogen Oxides; D011725:Pyridines; C043438:alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone; D014810:Vitamin E; D013311:Streptozocin; D045643:DNA Repair Enzymes; D001205:Ascorbic Acid