TY - JOUR
T1 - Influence of 3-aminobenzamide, an inhibitor of poly(ADP-ribose)polymerase, in the evaluation of the genotoxicity of doxorubicin, cyclophosphamide and zidovudine in female mice
AU - Yadav, L.
AU - Khan, S.
AU - Shekh, K.
AU - Jena, G. B.
N1 - Funding Information:
This work was supported by National Institute of Pharmaceutical Education and Research , S.A.S. Nagar, Mohali, Punjab 160062, India. The authors are grateful to Intas Pharmaceuticals Ltd. and Aurobindo Pharma Ltd., India for providing the generous gift sample of doxorubicin and zidovudine, respectively.
PY - 2014/8
Y1 - 2014/8
N2 - Testing new chemical entities for genotoxicity is an integral part of the preclinical drug-development process. Lowering the detection limit and enhancing the sensitivity of genotoxicity assays is required, as the standard test-battery fails to detect some carcinogens (non-genotoxic) and weak genotoxins. One of the mechanisms that affect the detection of weak genotoxins is related with the DNA-repair efficiency of the cell system used. In the present study, 3-aminobenzamide (3-AB, 30. mg/kg body-weight), a poly(ADP-ribose)polymerase inhibitor, was used to evaluate the DNA-damaging potential of zidovudine (AZT, 400. mg/kg. bw), doxorubicin (DOX, 5. mg/kg. bw) and cyclophosphamide (CP, 50. mg/kg. bw, as a positive control) and sucrose (SUC, 3. g/kg. bw, as a negative control) in Swiss female mice. The endpoints considered included micronucleus formation, DNA breakage (in peripheral blood lymphocytes, bone marrow and liver; comet assay) and chromosome aberrations, as well as immunohistochemistry of PARP-1 and phosphorylated histone H2AX (γ-H2AX). The results clearly indicate that the genotoxicity of zidovudine (AZT), doxorubicin (DOX) and cyclophosphamide (CP) was significantly increased in the combination treatments (3-AB. +. AZT, 3-AB. +. DOX, 3-AB. +. CP) as compared with the respective controls (treatment with AZT, DOX and CP alone). There was no increase in the genotoxicity per se after treatment with SUC, 3-AB or 3-AB. +. SUC, compared with the control (saline). Correlation analysis suggests that all genotoxicity parameters are well correlated with each other. The results clearly show that the genotoxicity of weak genotoxins can be enhanced and detected in the presence of 3-AB in mice. Thus, this approach can be used in the pre-clinical genotoxicity screening of weak genotoxins.
AB - Testing new chemical entities for genotoxicity is an integral part of the preclinical drug-development process. Lowering the detection limit and enhancing the sensitivity of genotoxicity assays is required, as the standard test-battery fails to detect some carcinogens (non-genotoxic) and weak genotoxins. One of the mechanisms that affect the detection of weak genotoxins is related with the DNA-repair efficiency of the cell system used. In the present study, 3-aminobenzamide (3-AB, 30. mg/kg body-weight), a poly(ADP-ribose)polymerase inhibitor, was used to evaluate the DNA-damaging potential of zidovudine (AZT, 400. mg/kg. bw), doxorubicin (DOX, 5. mg/kg. bw) and cyclophosphamide (CP, 50. mg/kg. bw, as a positive control) and sucrose (SUC, 3. g/kg. bw, as a negative control) in Swiss female mice. The endpoints considered included micronucleus formation, DNA breakage (in peripheral blood lymphocytes, bone marrow and liver; comet assay) and chromosome aberrations, as well as immunohistochemistry of PARP-1 and phosphorylated histone H2AX (γ-H2AX). The results clearly indicate that the genotoxicity of zidovudine (AZT), doxorubicin (DOX) and cyclophosphamide (CP) was significantly increased in the combination treatments (3-AB. +. AZT, 3-AB. +. DOX, 3-AB. +. CP) as compared with the respective controls (treatment with AZT, DOX and CP alone). There was no increase in the genotoxicity per se after treatment with SUC, 3-AB or 3-AB. +. SUC, compared with the control (saline). Correlation analysis suggests that all genotoxicity parameters are well correlated with each other. The results clearly show that the genotoxicity of weak genotoxins can be enhanced and detected in the presence of 3-AB in mice. Thus, this approach can be used in the pre-clinical genotoxicity screening of weak genotoxins.
KW - Chromosome aberration
KW - Comet
KW - Genotoxicity
KW - Micronucleus
KW - PARP inhibitor
KW - Weak genotoxins
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U2 - 10.1016/j.mrgentox.2014.04.020
DO - 10.1016/j.mrgentox.2014.04.020
M3 - Article
C2 - 25344158
AN - SCOPUS:84901801633
SN - 1383-5718
VL - 770
SP - 6
EP - 15
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
ER -