Approaches to High Throughput Toxicity ScreeningC. K. Atterwill, P. Goldfarb, W Purcell An integrated approach to in vitro toxicology and ADME screening using new technologies and discussing how they might be applied to the safety assessment of new pharamceutical products in drug discovery. |
Contents
Introduction | 7 |
Automation and Technology for HTS in Drug Development | 9 |
23 Automation of the biological assay | 13 |
24 Miniaturization trends in high throughput screening | 17 |
25 Conclusions | 27 |
Cytotoxicity and Mechanistic Studies in High Throughput Toxicity Screening | 31 |
32 Basal cytotoxicity screens | 32 |
33 Selective cytotoxicity | 34 |
52 Factors that determine the stress gene response | 75 |
53 The utility of stress genes as markers of cell toxicity | 78 |
54 Detection methods and screening for stress gene expression | 79 |
The Utility of Branched DMA bDNAI Assays in High Throughput Toxicity Screening | 91 |
62 Cellbased bDNA assay | 92 |
63 bDNA assays for toxicity screening | 95 |
64 bDNA assay performance | 97 |
66 Discussion | 103 |
34 Mechanisticallybased tests for toxicity | 35 |
35 Conclusions | 39 |
Gene Expression and its Applications to High Throughput Screens and Molecular Toxicology | 43 |
43 The advent of gene microarrays and their impact on toxicology | 44 |
44 Developing high throughput gene expression toxicity screens | 46 |
46 Differential display | 47 |
47 SAGE | 48 |
48 AFLP | 49 |
49 Measuring lexicologically relevant genes with microarrays | 51 |
410 Devising strategies for deriving toxicity rules | 52 |
411 Deriving gene expressiontoxicity rules | 53 |
412 High throughput gene expression systems | 54 |
413 Reporter constructs | 57 |
414 Validating gene expressiontoxicity rules | 59 |
416 Conclusions | 61 |
Note in proof | 66 |
Early Toxic Stressor Genes Modulation and Screening Technologies | 69 |
Methods for Assessing Apoptosis | 107 |
morphological features | 109 |
biochemical features | 111 |
a new challenge for toxicologists | 115 |
75 Morphological analysis of apoptotic cells | 118 |
76 Biochemical analysis of apoptosis | 119 |
77 Choice of methods to study druginduced apoptosis | 129 |
78 Conclusions | 130 |
Genetically Modified Cells to Assess Drug Metabolism In Vitro | 139 |
82 In vitro methods for prediction of human drug metabolism | 148 |
83 Heterologous expression systems for drug metabolizing enzymes | 150 |
The Future of High Throughput Screening and Pharmacotoxicology | 171 |
93 The validation of HTS systems | 174 |
References | 177 |
| 179 | |
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Approaches to High Throughput Toxicity Screening C. K. Atterwill,P. Goldfarb,W Purcell No preview available - 1999 |
Common terms and phrases
96-well plate acid activation analysis apoptosis apoptotic apoptotic cells approach assessment automation basal cytotoxicity bDNA assay Biochem biological branched DNA c-fos caspases cDNA cell lines cell types cell-based cellular chemical chromatin cisplatin coli combinatorial chemistry compounds culture cytochrome P450 detection differential display differentially expressed DNA damage DNA fragmentation drug development drug metabolism endpoints Figure fluorescent fold induction format function gene expression genomics glutathione heat shock protein hepatocytes heterologous expression high throughput screening high throughput toxicity human liver human P450s hybridization identified Ingelman-Sundberg inhibitors interactions Kass labelled levels mammalian measured methods microarrays microtitre plate molecular mRNA necrosis nuclear oligonucleotide oxidative P450 reductase Pharmacol plasma membrane polymorphic potential preclinical prediction primers quantitative receptor reporter gene response restriction enzyme sample sequence signal amplification specific stress gene studies substrate target throughput toxicity screens tion tissue toxicity toxicology transcription factors vitro vivo xenobiotics yeast