Model Organisms in Drug Discovery

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paradoxical phenomenon that, on the one hand, Drosophila is widely recognized for its predictive power for human gene function, including genes involved in safeguarding DNA and chromosomes, yet, on the other hand, it lacks broad use in testing the genotoxicity of pharmaceutical compounds. The likely explanations are: the classical SLRL assay is complex, requires special training and facilities not available in most toxicology laboratories in industry and has some weaknesses; a genotoxicity test requires extensive evaluation before it becomes a standard test and only recently has such a level of validation been achieved for the SMART assays; and, most importantly, Drosophila assays are not yet included in recommendations or guidelines issued by international regulatory agencies, such as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). For example, in the ICH topic S2B, Genotoxicity: a Standard Battery for Genotoxicity Testing of Pharmaceuticals, three tests are recommended: a test for gene mutation in bacteria (such as the Salmonella Ames test); an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay; and an in vivo test for chromosomal damage using rodent hematopoietic cells. Even though it will take some time before Drosophila assays are included in the regulatory tests, they can be applied immediately in some toxicology studies in drug discovery. For example, for lead compound prioritization, rapid and inexpensive assays are preferred after in silico evaluation of the mutagenic potential of the compounds based on their chemical structures and prior experience. The SMART assays are perfectly fitted for this application, especially if higher throughput assay formats and fly handling methods are developed. Drosophila assays also may be used as complementary or confirmatory tests when ambiguous results are obtained by the standard guideline tests. In addition, as an excellent genetic, biochemical and molecular biological experiment system, Drosophila is well suited for studying the mechanisms of genotoxicity of an important compound. 4.2 Research tools in Drosophila studies Information resources RESEARCH TOOLS IN DROSOPHILA STUDIES 101 A century of innovative research and community effort has given Drosophila biologists a wide array of research tools. One of the most important research tools is the extensive information resource. Currently, the compiled information is primarily made available through the Internet and books. We list some of the major ones here.
102 DROSOPHILA AS A TOOL FOR DRUG DISCOVERY Internet resources . Flybase (www.flybase.org): the most comprehensive database about Drosophila . Berkeley Drosophila Genome Project (www.fruitfly.org): genomic sequences, cDNA collections, insertion sites of P element mutations, bioinformatic tools . NCBI Drosophila genome (www.ncbi.nlm.nih.gov/cgi-bin/Entrez/map00? taxid=7227) . EuGene: Genomic Information for Eukaryotic Organisms (iubio.bio. indiana.edu:8089/): abridged comparison of genes between different eukaryotic genomes . Drosophila homologs of human disease genes (homophila.sdsc.edu) . Interactive fly (sdb.bio.purdue.edu/fly/aimain/1aahome.htm) Book titles . Biology of Drosophila (Demerec, 1994) . The Genome of Drosophila melanogaster (Lindsley and Zimm, 1992) . Drosophila: a Laboratory Handbook and Manual (Ashburner, 1989) . The Development of Drosophila melanogaster (Bate and Martinez Arias, 1993) . The Genetics and Biology of Drosophila (Ashburner and Novitski, 1976) . Drosophila: a Practical Approach (Roberts, 1998) . Drosophila Cells in Culture (Echalier, 1997) . Fly Pushing: the Theory and Practice of Drosophila Genetics (Greenspan, 1997) . Drosophila Protocols (Sullivan et al., 2000) Balancer chromosomes Balancer chromosomes in Drosophila belong to a special set of utility chromosomes that have multiple inversions to suppress recombination with the homologous chromosome, they are homozygous lethal or sterile and they
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Model Organisms in Drug Discovery M
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Copyright u 2003 John Wiley & Sons
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Contents List of contributors .....
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CONTENTS ix 7 Genetics and Genomics
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List of Contributors Hector Beltran
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LIST OF CONTRIBUTORS xiii Stefan Sc
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1 Introduction to Model Systems in
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Organism INTEGRATING MODEL ORGANISM
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INTEGRATING MODEL ORGANISM RESEARCH
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INTEGRATING MODEL ORGANISM RESEARCH
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10 GROWING YEAST FOR FUN AND PROFIT
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3 Caenorhabditis elegans Functional
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THE DRUG DISCOVERY PROCESS 43 thoug
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multivulva phenotype of Ras gain-of
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disease. These molecular targets ar
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Page 63 and 64: signaling pathway. The third catego
Page 65 and 66: FROM DISEASE TO TARGET 55 resistant
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Page 71 and 72: emerging technologies. Forward gene
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Page 85 and 86: REFERENCES 75 de Montigny, C., Blie
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Page 91 and 92: 82 DROSOPHILA AS A TOOL FOR DRUG DI
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Page 127 and 128: 5 Drosophila - a Model System for T
Page 129 and 130: EVOLUTIONARY CONSERVATION OF DISEAS
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Page 151 and 152: CHEMICAL GENETICS 143 acid identity
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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252 SATURATION SCREENING OF DRUGGAB
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280 INDEX bupropion 92 busulfan 143
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282 INDEX Dscam 171 dual-energy X-r
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284 INDEX L-685,818 16 lead discove
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286 INDEX protein function 19-22 pr
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288 INDEX yeast (continued) functio
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