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Received for publication July 15, 2004.
Revised July 14, 2004.
Accepted for publication August 30, 2004.
The discovery of the multidrug resistance protein 1 (MDR1), an ATP-binding cassette transporter able to transport many anticancer drugs, represents a clinically relevant breakthrough in multidrug resistance. Although the overexpression of ABC transporters such as P-gp/ ABCB1, MRP1/ABCC1 or MXR/ABCG2 appears to be a major cause of failure in the treatment of cancer, acquired resistance to multiple anticancer drugs may also be multifactorial, involving alteration of detoxification processes, apoptosis, DNA repair, drug uptake, and overexpression of further ABC transporters. We created a microarray platform to evaluate relative levels of transcriptional activation among genes involved in various mechanisms of resistance. In the ABC-ToxChip, a comprehensive set of genes important in toxicological responses (2,200 cDNA probes together with ~18,000 oligonucleotide probes) are complemented with probes specifically matching ABC transporters as well as oligos representing 18,000 unique human genes. By comparing the transcriptional profiles of KB-3-1 and DU-145 cells to resistant derivatives selected in colchicine (KB-8-5), and 9-nitro-camptothecin (RCO.1), respectively, we demonstrate that ABC transporters (ABCB1/MDR1 and ABCC2/MRP2, respectively) show dramatic overexpression, whereas the glutathione S-transferase gene (GST-Pi) shows the strongest decrease among the 20,000 genes studied. The results were confirmed by quantitative RT-PCR and immunohistochemistry. These results suggest that custom-made, dedicated microarrays will be helpful to elucidate mechanisms leading to anticancer drug resistance.
Key words:
MDR/p-Glycoprotein, Regulation - xenobiotic, Glutathione, Resistance
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