Fundamentals Of Genetic Toxicology In The Pharmaceutical Industry Sept 2010

Fundamentals of Genetic Toxicology in the Pharmaceutical Industry Prepared by: David Amacher, Ph.D, DABT www.tigertox.com

What is Genetic Toxicology? ,[object Object],[object Object],[object Object],[object Object]

Genotoxic Classification Scheme ,[object Object],[object Object],[object Object],Microlesions Base-pair substitution mutations Frameshift mutations Macrolesions [cytologically visible] Numerical changes in chromosomes Stuructural changes in chromosomes Mutation [Qualitative change in 1 or a few nucleotide pairs] [Quantitative change in 1 or a few nucleotide pairs] Diagram from Bruswick, D.J. Alterations of germ cells leading to mutagenesis and their detection. Environ. Health Perspect. 24(1978):105-112.

Mechanisms for Genetic Damage ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Types of Genetic Damage ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

DNA Repair ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

DNA Repair Mechanisms ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

DNA Repair Mechanisms ,[object Object],[object Object]

Testing Requirements ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Special Requirements for Testing during Preclinical Drug Development ,[object Object],[object Object],[object Object],[object Object]

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

The standard test battery ,[object Object],[object Object],[object Object]

The standard test battery ,[object Object],[object Object],[object Object],[object Object],ADME = absorption, distribution, metabolism, and excretion.

Assays for Detecting DNA Damage & Repair ,[object Object],[object Object],[object Object]

Assays for Detecting DNA Damage & Repair ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Options for the standard battery ,[object Object],[object Object],[object Object],[object Object]

Options for the standard battery ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Outcomes & Follow-up ,[object Object],[object Object],[object Object],[object Object]

Confounding Factors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Rationale for Early Genetic Toxicology Evaluation (Screening Assays) ,[object Object],[object Object],[object Object]

Discovery/Lead Optimization Screening Assays ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Rapid Pre-screening Methods ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Suggested sources for further reading ,[object Object],[object Object],[object Object],[object Object]

Further Information ,[object Object],[object Object],[object Object]

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Mammalian Somatic Cell Cycle ,[object Object],[object Object],[object Object],[object Object],[object Object],Referenced from http://bit.ly/byhKxT on 19 Sept 2010. Meiosis, which occurs only in germ cells, is the process of nuclear division that reduces the number of chromosomes by half.

Genotoxicity ICH Regulatory Guidelines ,[object Object],[object Object]

Fundamentals Of Genetic Toxicology In The Pharmaceutical Industry Sept 2010

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