A lot of compounds, although efficacious, may fail to meet the acceptable toxicity profile.
Toxicity profiling and testing is therefore an important facet of drug development. The objective is to ensure that the test substance is safe for further preclinical/clinical development.
Drugs research and development cost over $145 billion every year in the US only. One of the key contributors to these rising costs is unacceptable drug safety profile either detected during Phase 1 Clinical Trial (50-60%) or during Phase IV Post marketing surveillance where some severe side effects were unnoticed during the phase I clinical trial. This is what makes toxicity profiling so important. Of note, it has been described that in 30% of the studied cases the animals showed a toxic effect on a different organ compared to human (https://www.gwern.net/docs/dnb/2000-olson.pdf)
A549 cells were treated with drug compounds at 8 different concentrations. Both Cell Viability and Cytotoxicity of the cells post treatment was assessed using CellTitre-Glo and LDH respectively. Staurosporine (positive compound control) showed a significant reduction in cell viability when compared to untreated or vehicle control (***p<0.001; ±SEM).
HeLa cells were treated with Staurosporine for 4 hours at concentrations of: 10µM, 5µM, 2µM, 1µM, 500nM, 250nM, and 125nM. The Caspase-Glo 3/7® Reagent was added directly to cells in 96-well plates and incubated at room temperature for 30 minutes before recording luminescence (RLU). Each point represents the average of 3 replicates (error bars represent ±SEM).
Cytotoxic profile of a test antibody (1°Ab) in the presence of 2° antibody conjugated with-MMAE toxin. The viability of Kasumi-3 was analysed using Cell-Titer Glo Luminescence assay. A statistically significant decrease in Kasumi-3 cell viability was observed with concentrations above 0.01 nM test antibody in presence of 2°Ab-MMAE when analysed using One-way ANOVA, followed by Dunnett’s post-hoc multiple comparison test (*p<0.02; **p<0.005; ***p<0.0003, <0.0001; ±SEM).
|Acute kidney disease||Chronic kidney disease||Nephrotoxicity|
|Neutrophil gelatinase-associate lipocalin (NGAL)||Asymmetric dimethylarginine (ADMA)||N-acetyl-β-D-glucosaminidase (NAG)|
|interleukin-18 (IL18)||Neutrophil gelatinase-associate lipocalin (NGAL)||Glutathione S-transferases (GST)|
|Kidney Injury Molecule-1 (KIM1)||Kidney Injury Molecule-1 (KIM-1)||Gamma-glutamyltransferase (GGT)|
|Cystatic C (CST3)||Liver-type Fatty acid binding protein (L-FABP)||Kidney Injury Molecule-1 (KIM1)|
|Liver-type Fatty acid binding protein (L-FABP)||Lactic dehydrogenase (LDH)|
|Insulin like growth factor binding protein (IGFBP7)|
|Tissue metallopeptidase inhibitor 2 (TIMP-2)|
|Collagen IV||Epithelial growth factor||Clusterin|
|Cystatin C||Interferon gamma-induced protein 10||Cystatin C|
|Glutathione S-transferases||Kidney Injury Molecule-1||Glutathione S-transferases|
|Interferon gamma-induced protein 10||Lipocalin-2||Interferon gamma-induced protein 10|
|Kidney Injury Molecule-1||Osteopontin||Kidney Injury Molecule-1|
|Liver-type Fatty acid binding protein||β-2-Microglobulin||Osteopontin|
|Macrophage activator protein||Tissue metallopeptidase inhibitor 2||Tissue metallopeptidase inhibitor 2|
|Matrix Metalloproteinases (MMP9)||Vascular Endothelial Growth Factor||Vascular Endothelial Growth Factor|
|Osteopontin||Interleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)||Interleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)|
|Renin||Trefoil factor 3|
|Trefoil factor 3|
|Heat Shock Protein 70 (HSP70)|
|Interleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)|
|Liver-Type Arginase 1 (ARG1)||Liver-Type Arginase 1 (ARG1)|
|Malate dehydrogenase 1 (MDH1)||aspartate transaminase 1 (GOT1)|
|α-glutathione S-transferase (GSTα)||α-glutathione S-transferase (GSTα)|
|Sorbitol Dehydrogenase (SDH)||Sorbitol Dehydrogenase (SDH)|
|5′-Nucleotidase/CD73 (5’-NT)||5′-Nucleotidase (5′-NT/CD73).|
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