Pharmaceuticals genotoxicity assessment

Muller, L., and Kasper, P. (2000). Human biological relevance and the use of threshold-arguments in regulatory genotoxicity assessment Experience with pharmaceuticals. Mutat Res 464, 19-34. 

I. Y. Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ. Mol. Mutagen. 2004,... 

Examination of genotoxicity of pharmaceuticals is required to assess the interaction of the drug with DNA. These studies are generally not applicable to immunotoxins. Unlike chemotherapeutics that cause cell death through DNA interaction, immunotoxins mediate cell death by preventing protein synthesis. However, immunotoxins use a linker to connect the toxin to the antibody that may need to be examined if it is an organic linker and has the ability to bind DNA (per ICH S6). The majority of immunotoxins use either a nonreducible thioether linker for intact toxins or a disulfide bond for A chains and ribosome-inactivating proteins and do not interact with DNA. 

Chemical Induction of Micronucleated Polychromatic Erythrocytes in Mouse Bone Marrow Cells Carcinogenicity Assessment ICH S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals and ICH S2B Genotoxicity A Standard Battery of Genotoxicity Testing of Pharmaceuticals 2 -4 4-8 15,000-25,000... 

Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum IY (2004) Assessment of the sensitivity of the computational programs DEREK, TOPKAT and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ Mol Mutagen 43 143-158 Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors. In the series of Methods and Principles in Medicinal Chemistry, Vol. 11. Wiley VCH Weinheim... 

V. Because pharmaceuticals are normally tested for toxicity in rodent repeated dose toxicity tests and because there is no longer a requirement for an acute high dose rodent toxicity test, the assessment of genotoxicity (e.g., bone marrow micronucleus test or other tissue/endpoint) should be integrated, if feasible, into the rodent repeated dose toxicity study to optimize animal usage. 

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