Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10915050 | Mutation Research/Genetic Toxicology and Environmental Mutagenesis | 2005 | 13 Pages |
Abstract
The boron neutron capture (BNC) reaction results from the interaction of 10B with low-energy thermal neutrons and gives rise to highly damaging lithium and alpha-particles. In this work the genotoxicity caused by the BNC reaction in V79 Chinese hamster cells was evaluated in the presence of poly(ADP-ribosyl)ation inhibitors. Poly(ADP-ribose) polymerase-1 (PARP-1), the most important member of the PARP enzyme family, is considered to be a constitutive factor of the DNA damage surveillance network present in eukaryotic cells, acting through a DNA break sensor function. Inhibition of poly(ADP-ribosyl)ation was achieved with the classical compound 3-aminobenzamide (3-AB), and with two novel and very potent inhibitors, 5-aminoisoquinolinone (5-AIQ) and PJ-34. Dose-response increases in the frequencies of aberrant cells excluding gaps (%ACEG) and chromosomal aberrations excluding gaps per cell (CAEG/cell) were observed for increasing exposures to the BNC reaction. The presence of 3-AB did not increase the %ACEG or CAEG/cell, nor did it change the pattern of the induced chromosomal aberrations. Results with 5-AIQ and PJ-34 were in agreement with the results obtained with 3-AB. We further studied the combined effect of a PARP inhibitor and a DNA-dependent protein kinase (DNA-PK) inhibitors (3-AB and wortmannin, respectively) on the genotoxicity of the BNC reaction, by use of the cytokinesis-block micronucleus assay. DNA-PK is also activated by DNA breaks and binds DNA ends, playing a role of utmost importance in the repair of double-strand breaks. Our results show that the inhibition of poly(ADP-ribosyl)ation does not particularly modify the genotoxicity of the BNC reaction, and that PARP inhibition together with a concomitant inhibition of DNA-PK revealed barely the same sensitizing effect as DNA-PK inhibition per se.
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Authors
Nuno G. Oliveira, Matilde Castro, António S. Rodrigues, Isabel C. Gonçalves, Célia Martins, José M. Toscano Rico, José Rueff,