Testing for the potential of drugs to cause damage to DNA is an essential component
of any pre-clinical testing program. Furthermore the screening for genetic toxicity
plays an important role in choosing a lead candidate during early drug development.
Literature reports put the incidence of positive in vitro genetic toxicology
results for pharmaceutical products at 20-25%. Genotoxicity findings can halt
further development or cause delays to clinical trials or even product registration.
It is therefore advisable to screen for genotoxic effects as early as possible
(see Discovery Services – Lead Optimisation).
For a new chemical entity (NCE ) the ICH guidelines recommend a minimum of
two in vitro tests prior to first human studies. These will be:
- Bacterial cell mutation (Ames test) plus, either one of
the following:
- Mammalian cell mutation (mouse lymphoma) or
- Chromosome aberration analysis (in human lymphocytes or CHL cells)
If there is a positive result in any of the in vitro assays, two in vivo tests will also be required prior to first human clinical trials.
Although not specifically required, we would routinely recommend at least one in vivo test is performed prior to phase I, usually the rodent micronucleus.
In the event of positive results being found, additional mechanistic investigations
may be helpful to elucidate the mechanisms by which genotoxic effects are seen.
Huntingdon Life Sciences has extensive experience in all the necessary regulatory
studies, across many compound classes, and can additionally provide an expert
review or consultancy service on request.
- Bacterial mutation (Ames)
- Mammalian cell mutation
- In vitro chromosome aberration
- In vitro and in vivo micronucleus
- In vitro and in vivo unscheduled DNA synthesis (UDS)
- In vitro micronucleus tests
- Fluorescence in situ hybridisation
- Aneuploidy assessment
- Mitogenesis and cell cycling by flow cytometry
- Apotosis
- Single cell gel electrophoresis (COMET) assay
- In vitro micronucleus tests
- Fluorescence in situ hybridisation
- Mini-Ames test
- Fluctuation tests
- SOS umuC reporter gene assay
- Mammalian cell mutation
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