Naslov
Irinotecan toxicity to human blood cells in vitro – relationships between various biomarkers

Autori
Kopjar, Nevenka ; Želježić, Davor ; Lucić Vrdoljak, Ana ; Radić, Božica ; Ramić, Snježana ; Milić, Mirta ; Gamulin, Marija ; Pavlica, Vesna ; Fučić, Aleksandra

Izvornik
Basic&Clinical Pharmacology&Toxicology (1742-7835) 100 (2007), 6; 403-413

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
irinotecan; in vitro toxicity; AChE; genotoxicity; comet assay test

Sažetak
Toxic effects of the antineoplastic drug irinotecan on human blood cells at concentrations 9.0 μ g/ml and 4.6 μ g/ml were evaluated in vitro. Using the alkaline and neutral comet assay significantly increased levels of primary DNA damage in lymphocytes were detected. The induction of apoptosis/necrosis, as determined by a fluorescent assay, was also notably increased. Cytogenetic outcomes of the treatment were assessed by the analysis of structural chromosome aberrations and FISH. Significantly higher incidence of chromatid breaks and complex quadriradials was observed. Painted chromosomes 1, 2, and 4 were equally involved in translocations, but only the chromosome 1 was involved in formation of quadriradials. SCE analysis was performed in parallel with the analysis of lymphocyte proliferation kinetics. The higher concentration of irinotecan caused almost seven-fold, while the lower one caused a five-fold increase of the basal SCE frequency, accompanied with significant lowering of the lymphocyte proliferation index. Using the cytokinesis-block micronucleus (MN) assay, a dose-dependent increase in MN frequency along with the formation of nuclear buds and nucleoplasmic bridges was noticed. Inhibitory effects of irinotecan on enzyme acetylcholinesterase (AChE) were studied in erythrocytes. An IC50 value of 5.0 x 10-7 was established. Irinotecan was found to be strong inhibitor of the ACh hydrolysis and caused a continuous decrease of catalytic activity of AChE. The results obtained on a single donor may contribute to the understanding of irinotecan toxicity, but further in vitro and in vivo studies are essential in order to clarify remaining issues, especially on possible inter-individual variability in genotoxic responses to the drug.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA