Beyond the Identification of Transcribed Sequences: Functional and Expression Analysis

9th Annual Workshop, October 28-31, 1999

Co-sponsored by the U.S. Department of Energy


ZHOU

Gene expression profiling in molecular pharmacology

Y. Zhou, U. Scherf, M. Waltham, W.C. Reinhold, L.H. Smith, J.K. Lee, D.A. Scudiero, E.A. Sausville, D. Ross1, M. Eisen1, D. Botstein1, P.O. Brown1, L. Miller, E. Liu and J.N. Weinstein

National Cancer Institute, Bethesda, Maryland, USA
1Stanford University Medical Center, Stanford, California, USA

High-density cDNA microarrays and oligonucleotide chips provide an opportunity to study gene expression in a parallel fashion, often thousands of genes at a time. In the context of molecular pharmacology, large scale gene expression profiling can be used to identify genes whose expression patterns predict the activity patterns of drugs. Since 1990, the National Cancer Institute's drug discovery program has used 60 cancer cell lines to screen more than 70,000 chemical compounds for anticancer activity. The resulting patterns of activity encode incisive information about mechanisms of drug action and resistance (Paull, et al., JNCI 81:1088, 1989; Weinstein, et al., Science 258:343, 1992 and 275:343, 1997). We have recently studied gene expression profiles of the 60 cancer cell lines using two-color fluorescence detection on glass slide cDNA microarrays containing approximately 9,000 genes (Ross, et al. and Scherf, et al., submitted). The results are, or will soon be, displayed at our web site (http://discover.nci.nih.gov).

Those studies delineated sensitivity to treatment. We are also analyzing in detail the molecular consequences of therapy as a function of dose and time after treatment for a selected drug-cell pair. Both types of experiments provide information potentially useful for delineation of molecular pathways, clinical selection of therapy, and discovery of new anticancer agents. Funded in part by a grant from the NCI Breast Cancer Think Tank.


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