Analysis of 75 marketed pharmaceuticals using the GADD45a-GFP 'GreenScreen HC' genotoxicity assay.
The GADD45a-GFP (GreenScreen HC) reporter assay detects genotoxic damage in the human lymphoblastoid TK6 cell line and gives positive results for all classes of genotoxin, including mutagens, aneugens and clastogens. In this study, a collection of 75 marketed pharmaceuticals were tested in the assay. Compounds in the collection represent a broad range of chemical structures, pharmacologies and therapeutic indications, including neoplasia and viral infection where positive genotoxicity results are often associated with the pharmacological activity. Based on the results of this study, two main conclusions can be drawn: (i) the GreenScreen HC is more predictive of in vivo genotoxicity (88%) and genotoxic carcinogenicity (93%) data than the any of the other regulatory in vitro genotoxicity assay and (ii) no compounds were uniquely positive in the GADD45a-GFP assay. This analysis therefore provides additional evidence to support the use of the GADD45a-GFP assay as an effective tool either in early genotoxic liability identification or non-clinical safety assessment of candidate pharmaceuticals during development.
Hastwell
Paul W
PW
Genetic Toxicology, GlaxoSmithKline plc, Hertfordshire SG12 0DP, UK. paul.w.hastwell@gsk.com
Webster
Thomas W
TW
Tate
Matthew
M
Billinton
Nicholas
N
Lynch
Anthony M
AM
Harvey
James S
JS
Rees
Robert W
RW
Walmsley
Richard M
RM
D001681:Biological Assay / Q000379:methods*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D006801:Humans; D040541:Marketing; D009152:Mutagenicity Tests / Q000379:methods*; D009687:Nuclear Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011237:Predictive Value of Tests; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D049452:Green Fluorescent Proteins; D009687:Nuclear Proteins; D004364:Pharmaceutical Preparations; C439070:GADD45A protein, human; D000097642:GADD45 Proteins