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ToxSci Advance Access originally published online on January 4, 2007
Toxicological Sciences 2007 97(1):21-26; doi:10.1093/toxsci/kfl192
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation Part III: The Comet Assay as an Alternative to In Vitro Clastogenicity Tests for Early Drug Candidate Selection

Irene Witte*, Ulla Plappert{dagger}, Hartmut de Wall* and Andreas Hartmann{dagger},1

* Institute for Biology and Environmental Sciences, University of Oldenburg, Germany {dagger} Novartis Pharma AG, Safety Profiling & Assessment, CH-4002 Basel, Switzerland

1 To whom correspondence should be addressed. Fax: +41 61-32-41565. E-mail: andreas.hartmann{at}novartis.com.

Received October 13, 2006; accepted November 28, 2006


  Abstract

Early screening of drug candidates for genotoxicity typically includes an analysis for mutagenicity in bacteria and for clastogenicity in cultured mammalian cells. In addition, in recent years, an early assessment of photogenotoxicity potential has become increasingly important. Also, for screening purposes, expert computer systems can be used to identify structural alerts. In cases where structural alerts are identified, mutagenicity testing limited to bacteria can be conducted. The sequence of computer-aided analysis and limited testing using bacteria allows for screening a comparatively large number of drug candidates. In contrast, considerably more resources, in terms of supplies, technical time, and the amount of a test substance needed, are required when screening for clastogenic activity in mammalian cells. In addition, the relatively large percentage of false positive results for rodent carcinogenicity associated with clastogenicity assays is of considerable concern. As a consequence, mammalian cell–based alternatives to clastogenicity assays are needed for early screening of mammalian genotoxicity. The comet assay is a relatively fast, simple, and sensitive technique for the analysis of DNA damage in mammalian cells. This assay seems especially useful for screening purposes because false positives associated with excessive toxicity appear to occur less frequently, only relatively small amounts of a test compound are needed, and certain steps of the test procedure can be automated. Therefore, the in vitro comet assay is proposed as an alternative to cytogenetic assays in early genotoxicity/photogenotoxicity screening of drug candidates.

Key Words: genotoxicity; chromosome aberration assay; micronucleus test; high-throughput.


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