ToxTracker® Assay for Mechanistic Insight into Genotoxic Properties of Compounds

ToxTracker® ACE can help identify genotoxic and non-genotoxic modes of action (MOA), including oxidative stress, protein misfolding, and general cellular stress. The unique combination of green fluorescent protein (GFP) reporter genes integrated into mouse-based embryonic stem cell lines allows for highly accurate identification of genotoxic carcinogens. The induction of GFP reporters by test compounds is efficiently measured across a broad concentration range using flow cytometry, resulting in quantitative data on dose-response relationships.

Moreover, an aneugenic clastogenic evaluation (ACE) is performed concurrently to detect aneugenic properties of a compound. These features make ToxTracker® ACE an ideal platform to quickly and accurately screen out genotoxic compounds, or as a GLP-compliant assay to support de-risk of adverse finding in regulatory assays.

Validation of the ToxTracker Assay: Testing of Blinded Compounds

Illustration of DNA.

Adverse genotoxicity often leads to termination of the drug development program. ToxTracker employs mouse stem cell lines with biomarkers that detects the mechanism of genotoxicity.

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There’s No Better Way to Screen for MOA

Diagram depicting the markers ToxTracker can identify that reveal genotoxic modes of action as well as non-genotoxic modes of action including DNA, protein, and oxidative damage

The unique assay combines six GFP reporter cell lines to discriminate between induction of DNA damage, activation of p53, induction of oxidative stress, and protein damage. Their collective induction profile provides mechanistic insight into specific genotoxic properties of compounds. The wild-type cell line is used to detect aneugenic compounds by evaluating DNA content of the cells.

Diagram of ToxTracker’s six fluorescent assay reporter cells and the genotoxic and non-genotoxic Modes of Action (MoA) the assay predicts

 

Key Benefits of Genotoxicity Testing with ToxTracker® ACE

  • Mechanistic insight into genotoxicity
  • Detection of aneugenic properties of compounds
  • Unsurpassed sensitivity (94%) and specificity (95%)
  • Predictor for regulatory in vitro and in vivo assays
  • Rapid and reliable three-part test
Test Name Sensitivity (%) Specificity (%)
ToxTracker® ACE 94 95
Chromosome Aberrations 79 55
Mammalian Mutation 81 48
Bacterial Reversion (Ames) 60 77
Micronucleus Test 79 54

 

Applications in Genotoxicity Testing and Assessment

  • Early non-regulatory preclinical development phase of pharmaceuticals applied as genotoxicity screen – ToxTracker® can predict, with high accuracy, the outcomes of the regulatory in vitro battery of genotoxicity testing (positive in mutation or chromosome damage tests).
  • GLP-compliant assay as follow up of the regulatory in vitro battery of genotoxicity assays to provide insight into MOA of genotoxic compounds – This information can be used in a weight-of-evidence approach to claim a safety threshold limit of exposure.
  • It can be used as a prescreen or mechanistic follow up of the regulatory in vitro genotoxicity testing for cosmetic ingredients and final products.
  • It’s useful in mechanistic studies and read-across approaches for retesting marketed chemicals under REACH and novel substances.
  • In vitro indicator test for numerous non-genotoxic mechanisms of toxicity that are associated with an increased carcinogenicity hazard.

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Frequently Asked Questions (FAQs) about Genotoxicity Testing with ToxTracker® ACE Assays

  • What is ToxTracker®?

    ToxTracker® is a stem cell-based assay used in genotoxicity testing that provides mechanistic insight into specific properties of compounds.

  • How does the ToxTracker® assay compare to other genotoxicity testing methods?

    The ToxTracker® assay is highly specific and sensitive. It uses one test to present results for your genotoxicity testing and assess oxidative stress, protein misfolding, and cellular stress for your pharmaceutical compounds and chemicals.

  • What is ACE?

    It is an aneugenic clastogenic evaluation performed concurrently with ToxTracker® to detect aneugenic properties of a compound by evaluating the DNA content of cells.

  • How long does it take to run a ToxTracker® ACE test?

    This is the typical timeline for a ToxTracker® ACE test:

    • Dose range finding – One week
    • Main test – One week after dose range binding
    • Results – 1-2 weeks after main test
    • Draft report – 3-4 weeks after assay is completed