Genotoxicity of idarubicin and its modulation by vitamins C and E and amifostine.
Idarubicin is an anthracycline anticancer drug used in haematological malignancies. The main side effect of idarubicin is free-radicals based cardiotoxicity. Using the comet assay we showed that the drug at concentrations from the range 0.001 to 10 microM induced DNA damage in normal human lymphocytes, measured as the increase in percentage of DNA in the tail (% tail DNA). The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Recognised cell protector, amifostine at 14 mM decreased the mean % tail DNA of the cells exposed to idarubicin at all tested concentrations of the drug. So did vitamin C at 10 microM, but vitamin E (alpha-tocopherol) at 50 microM increased the % tail DNA. Lymphocytes exposed to idarubicin and treated with endonuclease III, formamidopyrimidine-DNA glycosylase and 3-methyladenine-DNA glycosylase II, enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes. Pretreatment of lymphocytes with nitrone spin traps, N-tert-butyl-alpha-phenylnitrone and alpha-(4-pyridil-1-oxide)-N-tert-butylnitrone decreased the extent of DNA damage evoked by idarubicin. To discuss the influence of vitamins and amifostine in cancer cells we used also murine pro-B lymphoid BaF3 transformed with BCR/ABL oncogene. These cells can be treated as model cells of human acute myelogenous leukemia. The response of these cells to vitamin E was quantitatively the same as human lymphocytes. However, vitamin C did not exert any effect on DNA damage and amifostine, in spite to normal lymphocytes, potentiated this effect. The results obtained suggest that reactive oxygen species, including free radicals, may be involved in the formation of DNA lesions induced by idarubicin. The drug can also methylate DNA bases. Our results indicate that not only cardiotoxicity but also genotoxicity and in consequence induction of secondary malignancies should be taken into account as diverse side effects of idarubicin. Amifostine may potentate DNA-damage effect of idarubicin in cancer cells and decrease this effect in normal cells. Vitamin C can be considered as protective agents against DNA damage in normal cells in persons receiving idarubicin-based chemotherapy, but the use of vitamin E cannot be recommended and at least needs further research.
Błasiak
Janusz
J
Department of Molecular Genetics, University of Lodz, Banacha 12/16, Poland. januszb@biol.uni.lodz.pl
Gloc
Ewa
E
Woźniak
Katarzyna
K
Młynarski
Wojciech
W
Stolarska
Małgorzata
M
Skórski
Tomasz
T
Majsterek
Ireneusz
I
D000328:Adult; D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004706:Endodeoxyribonucleases / Q000494:pharmacology; D006801:Humans; D015255:Idarubicin / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D009153:Mutagens; D014815:Vitamins; D014810:Vitamin E; D004706:Endodeoxyribonucleases; D004999:Amifostine; D001205:Ascorbic Acid; D015255:Idarubicin