DNA damage and repair in human lymphocytes exposed to three anticancer platinum drugs.
Cisplatin is a widely used anticancer drug, but its application is limited due to severe side effects. To reduce these effects, many other platinum drugs have been synthesized. In the present work comparative analysis of the toxicity of cisplatin, oxoplatin, and a conjugate (NH(3))(2)Pt(SeO(3)) (Se-Pt) in terms of cell viability, DNA binding, and DNA damage and repair in human lymphocytes was performed using the Trypan blue exclusion test, atomic absorption spectroscopy, and the comet assay, respectively. Cisplatin and oxoplatin did not cause a significant change in the viability of the lymphocytes even at the highest used concentration (750 microM), but the conjugate dramatically diminished viability at 100 microM only about 60% of the lymphocytes were viable (P < 0.05), and at 750 microM, less than 20% (P < 0.001). Se-Pt bound to isolated DNA was about 100 times weaker than the remaining two compounds; the binding of cisplatin was about 30% stronger than oxoplatin. Cisplatin and oxoplatin formed crosslinks with DNA in lymphocytes, whereas the conjugate induced DNA strand breaks. The lesions evoked by cisplatin and oxoplatin were slowly removed, but damage induced by Se-Pt was not repaired after 5 h even at a drug concentration of 10 microM. Severe cytotoxic and genotoxic effects exerted by Se-Pt in normal human lymphocytes preclude its intravenous application in cancer therapy. Teratogenesis Carcinog. Mutagen. 20:119-131, 2000.
Blasiak
J
J
Department of Molecular Genetics, University of Lodz, Lodz, Poland. januszb@biol.uni.lodz.pl
Kowalik
J
J
Małecka-Panas
E
E
Drzewoski
J
J
Wojewódzka
M
M
D000328:Adult; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D020552:Comet Assay; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D018036:Selenium Compounds / Q000378:metabolism / Q000633:toxicity*
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018036:Selenium Compounds; C110743:selenium-cisplatin conjugate; D004247:DNA; D002945:Cisplatin; C043804:diamminedichlorodihydroxyplatinum IV