Year

2005

Type(s)

Journal Article

Author(s)

Czechowska, Agnieszka and Poplawski, Tomasz and Drzewoski, Jozef and Blasiak, Janusz

Source

Chemico-Biological Interactions, 152(2–3): 139—150, 2005

Url

http://www.sciencedirect.com/science/article/pii/S000927970500061X

BibTeX

BibTeX

BibTeX

@article{czechowska_imatinib_2005, title = {Imatinib ({STI}571) induces {DNA} damage in {BCR}/{ABL}-expressing leukemic cells but not in normal lymphocytes}, volume = {152}, issn = {0009-2797}, url = {http://www.sciencedirect.com/science/article/pii/S000927970500061X}, doi = {10.1016/j.cbi.2005.03.002}, abstract = {Imatinib (STI571) is a 2-phenylaminopyrimidine derivative used mostly in the treatment of chronic myeloid leukaemia. It targets the BCR/ABL oncogenic tyrosine kinase, inhibiting its activity. Using the alkaline comet assay we showed that STI571 at concentrations ranging from 0.2 to 2 μM induced DNA damage in human leukemic K562 and BV173 cells expressing the BCR/ABL oncogene, whereas it had no effect in normal human lymphocytes and leukemic CCRF-CEM cells without the expression of BCR/ABL. Imatinib did not induce DNA strand breaks in the direct interaction with DNA as examined by the circular plasmid relaxation assay. Because the extent of DNA damage observed in the neutral and pH 12.1 versions of the comet assay was much lesser than in the alkaline version, we concluded that the drug induced DNA alkali-labile sites rather than strand breaks. K562 cells were unable to repair H2O2-induced DNA damage during a 120-min incubation, if they had been preincubated with STI571, whereas normal lymphocytes did so within 60 min. Pre-treatment of K562 cells with Vitamins A, C and E reduced the extent of DNA damage evoked by STI571. Similar results brought experiments with the nitrone spin traps POBN and PBN, suggesting that free radicals may be involved in the formation of DNA lesions induced by STI571 in K562 cells. These cells exposed to imatinib and treated with endonuclease III, formamidopyrimidine-DNA glycosylase and 3-methyladenine-DNA glycosylase II, the enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes. Therefore, the mechanism of the anti-leukemic action of STI571 may involve not only the inhibition of BCR/ABL, but also DNA damage in the cells expressing this fusion protein. DNA damage induced by STI571 may follow from oxidative and alkylative base modifications.}, number = {2–3}, urldate = {2014-11-03}, journal = {Chemico-Biological Interactions}, author = {Czechowska, Agnieszka and Poplawski, Tomasz and Drzewoski, Jozef and Blasiak, Janusz}, month = apr, year = {2005}, keywords = {DNA Repair, bcr/abl, imatinib, sti571, K562 Cells, DNA Damage}, pages = {139--150}, file = {ScienceDirect Full Text PDF:C:\Users\Tomasz Poplawski\Zotero\storage\X2SRS5IC\Czechowska i in. - 2005 - Imatinib (STI571) induces DNA damage in BCRABL-ex.pdf:application/pdf;ScienceDirect Snapshot:C:\Users\Tomasz Poplawski\Zotero\storage\5ZKVQ6WQ\S000927970500061X.html:text/html}