Overview of Microarrays in Drug Discovery and Development

Jeffrey F. Waring1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.6
DOI:  10.1002/0471141755.ph0906s21
Online Posting Date:  July, 2003
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

With the sequencing of the human genome, new tools and technologies have been developed to identify and quantify global gene‐expression changes occurring in the cell. One of the main tools being utilized is microarray technology, which allows one to quantitate expression changes of thousands of genes in a single experiment. Microarrays allow researchers to gain an unprecedented understanding of the function and regulation of genes, and are transforming virtually all areas of biological research. In the drug‐discovery process, microarrays have the potential to play a role in all stages, from new target discovery through compound profiling and safety assessment. This overview highlights some of these studies and discusses how this technology is transforming the field of drug discovery and development.

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Microarrays: Past, Present, Future
  • Application of Microarrays to Drug Discovery
  • Future Directions
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Anderson, L. and Seilhamer, J. 1997. A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 18:533‐537.
   Augenlicht, L.H., Wahrman, M.Z., Halsey, H., Anderson, L., Taylor, J., and Lipkin, M. 1987. Expression of cloned sequences in biopsies of human colonic tissue and in colonic carcinoma cells induced to differentiate in vitro. Cancer Res. 47:6017‐6021.
   Bammert, G.F. and Fostel, J.M. 2000. Genome‐wide expression patterns in Saccharomyces cerevisiae: Comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol. Antimicrob. Agents Chemother. 44:1255‐1265.
   Bowtell, D.D.L. 1999. Options available—from start to finish—for obtaining expression data by microarray. Nat. Genet. 21:25‐32.
   Bulera, S.J., Eddy, S.M., Ferguson, E., Jatkoe, T.A., Reidel, J.F., Bleavins, M.R., and DeLaIglesia, F.A. 2001. RNA expression in the early characterization of hepatotoxicants in Wistar rats by high‐density DNA microarrays. Hepatology 33:1239‐1258.
   Burke, H.B. 2000. Discovering patterns in microarray data. Mol. Diagn. 5:349‐357.
   Cheung, V.G., Morley, M., Aguilar, F., Massimi, A., Kucherlapati, R., and Childs, G. 1999. Making and reading microarrays. Nat. Genet. 21:15‐19.
   Chiesi, M., Huppertz, C., and Hoffbauer, K.G. 2001. Pharmacotherapy of obesity: Targets and perspectives. Trends Pharmacol. Sci. 22:247‐254
   Clarke, P.A., Poele, R., Wooster, R., and Workman, P. 2001. Gene expression microarray analysis in cancer biology, pharmacology, and drug development: Progress and potential. Biochem. Pharmacol. 62:1311‐1336.
   Cristillo, A.D. and Bierer, B.E. 2002. Identification of novel targets of immunosuppressive agents by cDNA‐based microarray analysis. J. Biol. Chem. 277:4465‐4476.
   Cunningham, M.J. 2000. Genomics and proteomics: The new millennium of drug discovery and development. J. Pharmacol. Toxicol. Methods 44:291‐300.
   Drews, J. 2000. Drug discovery: A historical perspective. Science 287:1960‐1964.
   Eisen, M.B., Spellman, P.T., Brown, P.O., and Botstein, D. 1998. Cluster analysis and display of genome‐wide expression patterns. Proc. Natl. Acad. Sci. U.S.A. 95:14863‐14868.
   Friend, S.H. 2000. Genomic approaches to drug discovery. Adv. Oncol. 16:3‐11.
   Golub, T.R., Slonim, D.K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J.P., Coller, H., Loh, M.L., Downing, J.R., Caligiuri, M.A., Bloomfield, C.D., and Lander, E.S. 1999. Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring. Science 286:531‐537.
   Gong, C.X., Lidsky, T., Wegiel, J., Zuck, L., Grudke‐Iqbal, K., and Iqbal, K. 2000. Phosphorylation of microtubule‐associated protein tau is regulated by protein phosphorylase 2A in mammalian brain: Implications for neurofibrillary degeneration in Alzheimer's disease. J. Biol. Chem. 275:5535‐5544.
   Gygi, S.P., Rochon, Y., Franza, B.R., and Aebersold, R. 1999. Correlation between protein and mRNA abundance in yeast. Mol. Cell Biol. 19:1720‐1730.
   Hakak, Y., Walker, J.R., Li, C., Wong, W.H., Davis, K.L., Buxbaum, J.D., Haroutunian, V., and Fienberg, A.A. 2001. Genome‐wide expression analysis reveals dysregulation of myelination‐related genes in chronic schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 98:4746‐4751.
   Hughes, T.R., Marton, M.J., Jones, A.R., Roberts, C.J., Stoughton, R., Armour, C.D., Bennett, H.A., Coffey, E., Dai, H., He, Y.D., Kidd, M.J., King, A.M., Meyer, M.R., Slade, D., Lum, P.Y., Stepaniants, S.B., Shoemaker, D.D., Gachotte, D., Chakraburtty, K., Simon, J., Bard, M., and Friend, S.H. 2000. Functional discovery via a compendium of expression profiles. Cell 102:109‐126.
   Jiang, Y., Harlocker, S.L., Molesh, D.A., Dillon, D.C., Stolk, J.A., Houghton, R.L., Repasky, E.A., Badaro, R., Reed, S.G., and Xu, J. 2002. Discovery of differentially expressed genes in human breast cancer using subtracted cDNA libraries and cDNA microarrays. Oncogene 21:2270‐2282.
   Kitteringham, N.R., Powell, H., Clement, Y.N., Dodd, C.C., Tettey, J.N., Pirmohamed, M., Smith, D.A., McLellan, L.I., and Kevin, P.B. 2000. Hepatocellular response to chemical stress in CD‐1 mice: Induction of early genes and γ‐glutamylcysteine synthetase. Hepatology 32:321‐333.
   Lee, C.K., Klopp, R.G., Weindruch, R., and Prolla, T.A. 1999. Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390‐1393.
   Lee, M.T., Kuo, F.C., Whitmore, G.A., and Sklar, J. 2000. Importance of replication in microarray gene expression studies: Statistical methods and evidence from repetitive cDNA hybridizations. Proc. Natl. Acad. Sci. U.S.A. 97:9834‐9839.
   Lee, C.K., Weindruch, R., and Prolla, T.A. 2000. Gene‐expression profile of the ageing brain in mice. Nat. Genet. 25:294‐297.
   Lipshutz, R.J., Fodor, S.P.A., Gingeras, T.R., and Lockhart, D.J. 1999. High density synthetic oligonucleotide arrays. Nat. Genet. 21:20‐24.
   Lockhart, D.J. and Winzeler, E.A. 2000. Genomics, gene expression and DNA arrays. Nature 405:827‐836.
   Loring, J.F., Wen, X., Lee, J.M., Seilhamer, J., and Somogyi, R. 2001. A gene expression profile of Alzheimer's disease. DNA Cell Biol. 20:683‐695.
   Marcotte, E.R., Srivastava, L.K., and Quirion, R. 2001. DNA microarrays in neuropsychopharmacology. Trends Pharmacol. Sci. 22:426‐436.
   Marton, M.J., DeRisi, J.L., Bennett, H.A., Iyer, V.R., Meyer, M.R., Roberts, C.J., Stoughton, R., Burchard, J., Slade, D., Dai, H., Bassett, D.E., Hartwell, L.H., Brown, P.O., and Friend, S.H. 1998. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nat. Med. 4:1293‐1301.
   Medlin, J. 2001. Array of hope for gene technology. Environ. Health Perspect. 109:A34‐A37.
   Nadler, S.T. and Attie, A.D. 2001. Please pass the chips: Genomic insights into obesity and diabetes. J. Nutr. 138:2078‐2081.
   Nadler, S.T., Stoehr, J.P., Schueler, K.L., Tanimoto, G., Yandell, B.S., and Attie, A.D. 2000. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc. Natl. Acad. Sci. U.S.A. 97:11371‐11376.
   Nguyen, L.T., Ramanathan, M., Weinstock‐Guttman, B., Dole, K., Miller, C., Planter, M., Patrick, K., Brownscheidle, C., and Jacobs, L.D. 2000. Detection of cytochrome P450 and other drug‐metabolizing enzyme mRNAs in peripheral blood mononuclear cells using DNA arrays. Drug Metabol. Dispos. 28:987‐993.
   Pan, W., Lin, J., and Le, C.T. 2002. How many replicates of arrays are required to detect gene expression changes in microarray experiments? A mixture model approach. Genome Biol 3:Research0022.
   Patil, N., Berno, A.J., Hinds, D.A., Barrett, W.A., Doshi, J.M., Hacker, C.R., Kautzer, C.R., Lee, D.H., Marjoribanks, C., McDonough, D.P., Nguyen, B.T.N., Norris, M.C., Sheehan, J.B., Shen, N., Stern, D., Stokowski, R.P., Thomas, D.J., Trulson, M.O., Vyas, K.R., Frazer, K.A., Fodor, S.P.A., and Cox, D.R. 2001. Blocks of limited haplotype diversity revealed by high‐resolution scanning of human chromosome 21. Science 294:1719‐1723.
   Pinheiro, N.A., Caballero, O.L., Soares, F., Reis, L.F., and Simpson, A.J. 2001. Significant overexpression of oligophrenin‐1 in colorectal tumors detected by cDNA microarray analysis. Cancer Lett. 172:67‐73.
   Poland, A., Knutson, J., and Glover, E. 1985. Studies on the mechanism of action of halogenated aromatic hydrocarbons. Clin. Physiol. Biochem. 3:147‐154.
   Reilly, T.P., Bourdi, M., Brady, J.N., Pise‐Masison, C.A., Radonovich, M.F., George, J.W., and Pohl, L.R. 2001. Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem. Biophys. Res. Commun. 282:321‐328.
   Rockett, J.C. and Dix, D.J. 2000. DNA arrays: Technology, options and toxicological applications. Xenobiotica 30:155‐177.
   Scherf, U., Ross, D.T., Waltham, M., Smith, L.H., Lee, J.K., Tanabe, L., Kohn, K.W., Reinhold, W.C., Myers, T.G., Andrews, D.T., Scudiero, D.A., Eisen, M.B., Sausville, E.A., Pommier, Y., Botstein, D., Brown, P.O., and Weinstein, J.N. 2000. A gene expression database for the molecular pharmacology of cancer. Nat. Genet. 24:236‐244.
   Sherlock, G. 2000. Analysis of large‐scale gene expression data. Curr. Opin. Immunol. 12:201‐205.
   Shipp, M.A., Ross, K.N., Tamayo, P., Weng, A.P., Kutok, J.L., Aguiar, R.C., Gaasenbeek, M., Angelo, M., Reich, M., Pinkus, G.S., Ray, T.S., Koval, M.A., Last, K.W., Norton, A., Lister, T.A., Mesirov, J., Neuberg, D.S., Lander, E.S., Aster, J.C., and Golub, T.R. 2002. Diffuse large B‐cell lymphoma outcome prediction by gene‐expression profiling and supervised machine learning. Nat. Med. 8:68‐74.
   Soukas, A., Cohen, P., Socci, N.D., and Friedman, J.M. 2000. Leptin‐specific patterns of gene expression in white adipose tissue. Genes & Dev. 14:963‐980.
   Southern, E., Mir, K., and Shchepinov, M. 1999. Molecular interactions on microarrays. Nat. Genet. 21: 5‐10.
   Ulrich, R.G. and Friend, S.H. 2002. Toxicogenomics and drug discovery: Will new technologies help us produce better drugs? Nat. Rev. Drug Discov. 1:84‐88.
   Valery, C., Grob, J., and Verrando, P. 2001. Identification of cDNA microarray technology of genes modulated by artificial ultraviolet radiation in normal human melanocytes: Relation to melanocarcinogenesis. J. Invest. Derm. 117:1471‐1482.
   Walt, D.R. 2000. Techview: Molecular biology. Bead‐based fiber‐optic arrays. Science 287:451‐452.
   Wang, T., Fan, L., Watanabe, Y., McNeill, P., Fanger, G.R., Persing, D.H., and Reed, S.G. 2001. L552S, an alternatively spliced isoform of XAGE‐1, is overexpressed in lung adenocarcinoma. Oncogene 20:7699‐7709.
   Watanabe, C.M., Wolffram, S., Ader, P., Rimbach, G., Packer, L., Maguire, J.J., Schultz, P.G., and Gohil, K. 2001. The in vivo neuromodulatory effects of the herbal medicine Ginkgo biloba. Proc. Natl. Acad. Sci. U.S.A. 98:6577‐6580.
   Waring, J.F., Ciurlionis, R., Jolly, R.A., Heindel, M., and Ulrich, R.G. 2001a. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. Toxicol. Lett. 120: 359‐368.
   Waring, J.F., Jolly, R.A., Ciurlionis, R., Lum, P.Y., Praestgaard, J.T., Morfitt, D.C., Buratto, B., Roberts, C., Schadt, E., and Ulrich, R.G. 2001b. Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol. Appl. Pharmacol. 175:28‐42.
   Waring, J.F., Gum, R., Morfitt, D., Jolly, R.A., Ciurlionis, R., Heindel, M., Gallenberg, L., Buratto, B., and Ulrich, R.G. 2002. Identifying toxic mechanisms using DNA microarrays: Evidence that an experimental inhibitor of cell adhesion molecule expression signals through the aryl hydrocarbon nuclear receptor. Toxicology 181‐182:537‐550.
   Weindruch, R. and Walford, R.I. 1988. The Retardation of Aging and Disease by Dietary Restriction. C.C. Thomas, Springfield, Ill.
   Whitney, L.W., Becker, K.G., Tresser, N.J., Caballero‐Ramos, C.I., Munson, P.J., Prabhu, V.V., Trent, J.M., McFarland, H.F., and Biddison, W.E. 1999. Analysis of gene expression in multiple sclerosis lesions using cDNA microarrays. Ann. Neurol. 46:425‐428.
   Young, R.A. 2000. Biomedical discovery with DNA arrays. Cell 102:9‐15.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library