Drug Resistance which ABCG2/BCRP contributes

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1. Change of substrate specificity, according to single nucleotide polymorphisms (SNPs) of ABCG2/BCRPIt is thought that 141st amino acid mutation influences the translation as one of the causes of the relative resistance decreases seen with PC6/Q141K, and the protein expression decreased. However, the protein expression was expected and some factors were expected to exist to about 65% of PC-6/WT from about 35% it as for the decrease in the resistance degree. The 141st amino acid mutation appears especially at high frequency in the Japanese, and it is necessary to pursue this result further. Whether the 141st amino acid is an amino acid that exists in the ATP binding site, and the localization of the mutation might influences the function of ABCG2. Then, the mutation that exists in the ATP binding site and/or outside of cell, in the transmembrane domain was examined.2. Expression of ABCG2/BCRP in clinical specimenThe amount of expression of ABCG2mRNA was observed among 12 samples examin … More ed by a real-time PCR analysis and an example that was remarkably higher in the cancer organization than the normal tissue and lower in the cancer organization than the normal tissue was observed. It was guessed that normal organization excretion of anti-cancer drug to protect itself by high expression of ABCG2 in the normal tissue. Moreover, examples were seen expression whose one of this level is almost higher than that of the normal tissue in three examples and the cancer organizations in the normal tissue and the cancer organization were two examples. A state and malignancy of cancer, stage classifications, and the lymph node metastasis were various in each patient, so that the correlation of expression amount of ABCG2mRNA and the malignancy of cancer were not detected.3. Inhibition mechanism of ABCG2/BCRP inhibitor and examination of specificityWe showed that quercetin, nobobioshin, and ZD1839 inhibit the transport activity of ABCG2 strongly, and to overcome various anti-cancer drug resistance in the ABCG2 expression cell line. Then, the inhibition effect of the transport activity was examined by using the ABCG2 gene transfection membrane to examine these three kinds of drugs inhibit the transport activity of the CPT derivatives that showed the resistance to ABCG2 excessive expression cell, and whether overcome the resistance. As a result, three kinds of inhibitors strongly inhibit transport activity of each CPT derivatives. It was suggested that the CPT derivatives shows the resistance to ABCG2 excessive expression cell overcome the drug resistance by using these inhibitors together. Less