National Cancer Institute Ncis 60cell Screening And Gene Expression Data

The National Cancer Institute's (NCI's) 60-cell line drug discovery panel (NCI60) was developed as a tool to assess anti-cancer activity of compounds against a range of cell lines derived from different cancers, including lung, renal, colorectal, ovarian, breast, prostate, central nervous system, melanoma, and hematological malignancies (12). Chemicals that reduce the viability of the cell are tagged as potential leads for affecting particular pathways characteristic of each tumor cell's biology. The biological response of such a cell-based assay is rich in information because, in principle, the complete systems biology information is encoded in the assay.

Even though such data is far more complicated and harder to interpret than a non-cellular, direct molecular binding assay, the ability to monitor a complete biological system over a number of genetically different cell lines offers advantages when studying mechanisms of drug action. The difference in cellular response to a drug is reflected in this biological response profile, ultimately encoding the underlying genetic difference responsible for the varied response.

The screening data consists of concentration values (GI50) for each cell line at which the drug results in a 50% reduction in the net protein increase relative to untreated control cells. In this assay the cells are inoculated onto a standard microtiter plate (typically 20,000 cells/well) and then pre-incubated for 24 hr in the absence of drug. Test agents are then added in five 10-fold dilutions starting from the highest soluble concentration, and incubated for a further 48 hr. Finally the cells are fixed in situ, washed, dried and sulforhodamine B is added. After further washing and drying the stained cells are solu-bilized and measured spectrophotometrically on automated plate readers interfaced to a computer.

From the relative growth inhibition compared to non-exposed cells, a dose-response curve is constructed, and the concentration at which 50% growth inhibition (GI50) is achieved is recorded. The log-transformed concentration for each cell line is recorded and can then be retrieved or visually inspected as a mean graph. Other end-points such as TGI and LC50 are also retrievable from the data. Because an individual GI50 concentration for a particular cell line may not be informative in itself, it is the differential pattern of the log-transformed concentrations across all cell lines that carries characteristic information about possible mechanisms of drug action. This pattern of GI50 measurements across the tumor cell lines, the biological response profile, has proven useful for identifying mechanisms of action for drug classes, and aids in the classification of novel drugs submitted to the NCI's tumor screen (13,14,15). The NCI60 screen has been operational since 1990 and has screened over 100,000 compounds.

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