Genotoxic agents or chemicals can cause inheritable altered traits, affect DNA and alter chromosome behaviours. The use of genetic toxicology testing enables early identification and screening for these genotoxins. Various testing tools enable qualitatively defined yes or no answers and mode-of-action evaluations of benefit when used extensively through early-stage drug discovery and assessment.
Identifying the toxicity of compounds and their potentially different effects on human subtypes or is necessary for drug development or testing the potential genotoxicity of new chemicals or properties. Genotoxicity covers a range of modes of action that may have adverse outcomes based DNA altering properties. DNA damage or mutation may result in a permanent structure or content change depending on its exposure conditions, such as metabolism, oxidative stress defence mechanisms and DNA repair. Testing for properties that can lead to cancers, inherited mutations, ageing, diseases and developmental toxicology is a crucial early step in identifying new drugs, chemicals or products.
Those in drug discovery must, therefore, understand the potential for harmful effects from our creations. Using Genetic toxicology screening could be the answer to many of the challenges drug manufacturers face, so here, we take a look at the benefits.
What can Genetic Toxicology Screening do?
Genetic toxicology screening identifies liabilities and potential outcomes. Chemical screening early in a developmental phase characterises the safety profile of the chemical series, thus, providing answers that can shape future development and reduce the risk of late-stage toxicology failure. Toxicologists have the opportunity to identify any changes necessary, determine associated risks and the impact on program success using the test results. Further mode-of-action assessments will aid decision making and future requirements by identifying at what dose adverse results may be obtained. Let’s take a look at two particular assay tests used to identify genotoxic effects of compounds.
BlueScreen HCTM assay can detect substances acting by all genotoxicity mechanism, requiring as little as 5mg of human-derived test compound. The 96 well in vitro GADD45-alpha gene reporter assay identifies the test substances’ ability to create a detectable luciferase signal. This accumulation of Gaussia luciferase is proportional to the levels of DNA damage that could occur to inform viability assessments.
MultiFlow® assay testing can identify misleading positives that may be secondary to cytotoxicity. It is regularly used and recognised as a primary screening tool; however, it is also of considerable benefit when positive in vitro results have been identified. This flow cytometric test enables fast predictions of the mode of action using statistical methods. It allows for risk and reward assessments to inform decisions and predict project outcomes.
The 24-well Ames assay is similar to the traditional Ames test but conducted on 1/20th of the surface area, and using reduced numbers of strains. This allows for prediction of the regulatory assay result using as little as 20 mg of test item.
The 96-well in vitro micronucleus assay (MNT) is a used to detect clastogenic or aneugenic modes of action. A miniaturised version of the regulatory assay, it is assessed using the same methodology (slide scoring), allowing for screening using far less test compound.
Genetic toxicology screening with a combination of the above assays allows for the assessment of all genotoxicity mechanisms. Testing methods incorporating FISH techniques within the MNT screen allow labelling of centromeres. Positive results can be identified as clastogenic or aneugenic mechanisms. Such benefits deliver comprehensive genetic toxicology predictions during the early stage of drug discovery. The chances of project success are increased when hurdles are identified and can either be overcome or signal a need to discontinue further development.
The ability to carry out predictive testing early in the developmental stage is a crucial benefit. Identifying genotoxins early in the development process can reduce much of the time progressing projects that may reach unacceptable conclusions. Mode of action testing can rescue previously failed drugs by identifying the point at which mutagens or cell structures change, allowing for adjustments or acceptable risk levels to be identified.
Highly accurate and quickly delivered results using cost-effective genotoxicity testing reduces risks for toxicologists, allowing them to shape risk assessments and rule out hazards during drug and chemical development.