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2004 Publication

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Predicting Drug Sensitivity and Resistance: Profiling ABC Transporter Genes in Cancer Cells

Gergely Szakács1, Jean-Philippe Annereau1, Samir Lababidi2, Uma Shankavaram2, Angela Arciello1, Kimberly J. Bussey2, William Reinhold2, Yanping Guo3, Gary D. Kruh3, Mark Reimers2, John N. Weinstein2, and Michael M. Gottesman1

1Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, MD, 20892 USA
2Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD, 20892 USA
3Medical Science Division, Fox Chase Cancer Center, Philadelphia, PA 19111 USA

2004 Cell PressPII:Section: Cancer Cell, Vol 6, 129-137, August 2004

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Abstract: For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the growth inhibitory profiles of 1,429 candidate anticancer drugs tested against the cells, we identified which transporters are more likely than others to confer resistance to which agents. Unexpectedly, we also found and validated compounds whose activity is potentiated, rather than antagonized, by the MDR1 multidrug transporter. Such compounds may serve as leads for development.

Supplemental Data:

Supplemental Figure S1. Structures of the compounds studied

Various cancer cells

A: Structures of the 17 candidate MDR1-substrates shown in Table S6. The structure of the 18th candidate ABCB1 substrate (NSC 652903) was not available from DTP.
B: Structure of the ABCC2-substrate NSC 641281.
C: Structure of the ABCC11-substrate NSC 671136.
D: Structure of NSC 73306.

Supplemental Figure S2. Expression of ABCG2 mRNA and protein in the 60 cell lines

ABCG2 expression table

mRNA expression values (horizontal bars) are taken from Supplemental Table S1. Cell lines indicated by black bars were shown to express "considerably high" protein levels by Western blotting (Imai et al, 2002).

Supplemental Table S1 (Microsoft Excel).(Text).  Expression of ABC transporters in the 60 cell lines.
Crossing point values were mean centered across the cells and across the transporters, then multiplied by -1 so as to reflect expression levels. Data on ABCA13 expression were taken from Prades et al., 2002.

Supplemental Table S2 (PDF). Clusters observed after hierarchical agglomerative clustering of cell lines based on expression profiles, with average linkage algorithm and a distance metric of 1-r

Supplemental Table S3 (PDF). Genes statistically significantly associated with tissues of origin

Supplemental Table S4 (PDF). Association of selected genes with tissue types

Supplemental Table S5 (Microsoft Excel).(Text). Pearson correlation of the activity levels of 1430 compounds with the expression levels of the 48 ABC transporters

Supplemental Table S6 (PDF). List of the 130 drug-gene pairs showing significant inverse correlation (p < 0.0001)

Supplemental Table S7 (PDF).  List of the 47 ABC transporter genes, their accession numbers, and the primers used for real-time RT-PCR amplification

Supplemental Table S8 (PDF). Correlation of ABCB1 mRNA and protein expression in the 60 cell lines

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