Establishing connections between microarray expression data and chemotherapeutic cancer pharmacology.
We have investigated three different microarray datasets of approximately 6 K gene expressions across the National Cancer Institute's panel of 60 tumor cell lines. Initial assessments of reproducibility for gene expressions within each dataset, as derived from sequence analysis of full-length sequences as well as expressed sequence tags (EST), found statistically significant results for no more than 36% of those cases where at least one replicate of a gene appears on the array. Filtering the data based only on pairwise comparisons among these three datasets creates a list of approximately 400 significant concordant expression patterns. The expression profiles of these smaller sets of genes were used to locate similar expression profiles of synthetic agents screened against these same 60 tumor cell lines. A correspondence was found between mRNA expression patterns and 50% growth inhibition response patterns of screened agents for 11 cases that were subsequently verifiable from ligand-target crystallographic data. Notable amongst these cases are genes encoding a variety of kinases, which were also found to be targets of small drug-like molecules within the database of protein structures. These 11 cases lend support to the premise that similarities between expression patterns and chemical responses for the National Cancer Institute's tumor panel can be related to known cases of molecular structure and putative cellular function. The details of the 11 verifiable cases and the concordant gene subsets are provided. Discussions about the prospects of using this approach as a data mining tool are included.
Wallqvist
Anders
A
Science Applications International Corporation, Frederick, Maryland 21702, USA.
Rabow
Alfred A
AA
Shoemaker
Robert H
RH
Sausville
Edward A
EA
Covell
David G
DG
D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020224:Expressed Sequence Tags; D008040:Genetic Linkage; D006801:Humans; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D013223:Statistics as Topic; D015854:Up-Regulation
D000970:Antineoplastic Agents