Historical and current perspectives on genetic toxicology, with commentary and slides on assay predictivity and shortcomings, regulatory guidance, and high-throughput screens to enhance preclinical drug safety.
Fundamentals Of Genetic Toxicology In The Pharmaceutical Industry Sept 2010
1. Fundamentals of Genetic Toxicology in the Pharmaceutical Industry Prepared by: David Amacher, Ph.D, DABT www.tigertox.com
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13. Examples of Genetic Toxicology Assays CHO = Chinese Hamster Ovary, HGPRT = hypoxanthine-guanine phosphoribosyl transferase gene in CHO cells, SHE = Syrian Hamster Embryo, BALB = BALB/3T3 cell transformation assay, Comet = also called single cell gel electrophoresis (SCGE)., DNA = deoxyribonucleic acid. * ICH S2B assay ‡ Good correlation with carcinogenicity (see: Regul. Toxicol. Pharmacol. 44:83-96, 2006) † Poor correlation with carcinogenicity (see: Regul. Toxicol. Pharmacol. 44:83-96, 2006) Gene Mutations Chromosome Damage Primary DNA Damage Salmonella Mammalian Microsome (Ames) Assay * ‡ In vitro metaphase chromosomal aberrations * † Transformation Assays (BALB/c or SHE) Mouse Lymphoma TK Assay (MLA) * † In vitro micronucleus test Comet Assay for DNA strand breakage ( in vitro & in vivo ) CHO/HGPRT Assay In vivo metaphase chromosomal aberrations Alkaline Elution Assay for DNA strand breakage Transgenic Assays (e.g. Big Blue® mouse & rat, Muta™ Mouse, lacZ plasmid mouse) In vivo micronucleus test * ‡ Unscheduled DNA synthesis (UDS) ( in vitro & in vivo) . DNA covalent binding assay