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Bioinformatics Vol. 19 no. 17 2003
pages 2212-2224
© 2003 Oxford University Press

Linking the growth inhibition response from the National Cancer Institute's anticancer screen to gene expression levels and other molecular target data

Anders Wallqvist 1,*, Alfred A. Rabow 1, Robert H. Shoemaker 2, Edward A. Sausville 2 and David G. Covell 2

1 Science Applications International Corporation and 2 Developmental Therapeutics Program, National Cancer Institute at Frederick, NIH Frederick, MD 21702, USA

Received on December 20, 2002 ; revised on April 23, 2003 ; accepted on May 6, 2003

Motivation: Data mining tools are proposed to establish mechanistic connections between chemotypes and specific cellular functions. Drawing on a previous study that classified the cellular response patterns of growth inhibition measurements log( GI50) from the National Cancer Institute's (NCI's) anticancer screen, we have examined additional data for mRNA expression, sets of known molecular targets and mutational status against these same tumor cell lines to relate chemosensitivity more precisely to biochemical pathways.

Results: Our analysis finds that gene expression levels do not, in general, correlate with log(GI50) measurements, instead they reflect a generic toxic condition. Within the remaining set of non-generic conditions, examples were found where a correlation suggesting a biochemical basis for cellular cytotoxicity could be supported. These included reconfirmation of previously observed associations between mutant and wild-type status of p53, and chemosensitivity to alkylating agents, while extending these results to reveal associations with {gamma}-induced expressions of MDM2, WAF1 and GADD45, signals that were not apparent in measurements of basal mRNA expression levels for any of these genes. Additional examinations revealed that mRNA expression levels directly correlated with paclitaxel chemosensitivity to mitosis, while also identifying additional chemotypes as P-glycoprotein substrates. Our analysis revealed well-known direct associations between p16 mutant status and chemotypes implicated in cell cycle control, and extended these results to include expression levels for three additional tyrosine kinase proteins (TEK, transgelin and hCdc4). Links were also found that suggested associations between chemosensitivity and the endocrine, paracrine ligand–receptor loops, via expression of the adrenergic receptor, calcium second messenger pathways via expression levels of carbonic anhydrase and cellular communication pathways via fibrillin.

Contact: wallqvist{at}ncifcrf.gov

* To whom correspondence should be addressed.


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