Introduction

Genotoxic chemicals cause damage to DNA, which if is non-lethal and not repaired, causes heritable changes in the genetic material in germ cells and can lead to cancer. Genotoxins can have a number of effects, including forming DNA adducts, DNA cross-linking, DNA breaks and gene mutations, as well as causing larger structural effects such as sister chromatid exchange, micronuclei, chromosomal aberrations, and chromosome mutations. These effects can all be detected using different assays and, since genotoxins can act by one or more of a broad spectrum of effects, a battery of tests (including the Ames, Micronucleus and Comet assays) is needed to increase the sensitivity of their detection.

Moreover, pro-genotoxins, which require metabolic activation to the ultimate genotoxin, need the test system (e.g. PBMC, lymphocytes, TK6 etc) to include an exogenous metabolism source e.g. liver S9, or the target cells should themselves be metabolically active (only HepaRG™ cells fit this criterion so far).

Genotoxicity

In genetics, genotoxicity describes the property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, whereas not all genotoxic substances are mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.

To assay for genotoxic molecules, researchers assay for DNA damage in cells exposed to the toxic substrates. This DNA damage can be in the form of single- and double-strand breaks, loss of excision repair, cross-linking, alkali-labile sites, point mutations, and structural and numerical chromosomal aberrations. The compromised integrity of the genetic material has been known to cause cancer. As a consequence, many sophisticated techniques including Ames Assay, in vitro and in vivo Toxicology Tests, and Comet Assay have been developed to assess the chemicals' potential to cause DNA damage that may lead to cancer.

If a compound tests negative in the proposed battery but shows any evidence of tumor response, then it needs more extensive testing. It should be remembered that the completion of a genotoxicity battery is required before the initiation of phase II trials. The type of genotoxicity studies routinely conducted for small molecules are not applicable to biotechnology-derived pharmaceuticals.

Genotoxicity is a concern with antineoplastic agents, which may go on to cause other malignancies in the host. Dacarbazine has been shown in vitro in rodent cell assays to interact with the genetic material of normal cells. The mechanism by which dacarbazine exerts genotoxic effects is not well understood, though it may be due in part by the methylation of DNA. The dacarbazine intermediary causes methylation at the N7 and O6 positions, as previously discussed.

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Regards

Mary Wilson

Editorial office

Clinical Pharmacology and Toxicology Research

E-mail: pharmatoxicol@eclinicalsci.com