2005 Fiscal Year Final Research Report Summary
DNA-based diagnosis on responsibility for anticancer drugs by methylation-specific PCR for BCRP
| Project/Area Number |
16590437
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Nagasaki University |
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Principal Investigator |
TSUKAMOTO Kazuhiro Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (30253305)
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| Co-Investigator(Kenkyū-buntansha) |
SODA Hiroshi Nagasaki University, Hospital of medicine and Dentistry, Associate Professor, 医学部・歯学部附属病院, 助教授 (60244042)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Breast cancer resistance protein : BCRP / Methylation / Methylation-specific PCR / Prediction for responsibility of anticancer drugs / DNA-based diagnosis / Irinotecan : CPT-11 / Lung cancer / Colorectal cancer |
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| Research Abstract |
Breast cancer resistant protein (BCRP) functions as a drug efflux transporter that mediates drug resistance. Topoisomerase I inhibitors including SN-38 (an active metabolite of irinotecan) are substrates effluxed by BCRP. The underlying mechanisms for overexpression of BCRP during acquisition of drug resistance remain unclear. Then, treatment of non-BCRP-expressing small-cell lung cancer cells, PC-6, with DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, induced BCRP re-expression at the mRNA and protein levels. Bisulfite sequencing analysis and subsequent comparisons between bisulfite-modified and unmodified DNA sequences at CpG sites in the promoter region of BCRP revealed that both alleles at all 89 CpG sites were completely methylated in PC-6, while those at 79 CpG sites in BCRP-expressing resistant small-cell lung cancer cells, PC-6/SN2-5H, were unmethylated. These results indicate a correlation between demethylation of the promoter region of BCRP and BCRP re-expression, an
… More
d suggest one of mechanisms for SN-38 drug resistance.
Next, a methylation-specific PCR (MSP) method for BCRP was established based on the sequences of BCRP in the methylated and methylated regions. MSP method revealed an inverse correlation between methylation status of the promoter region of BCRP and expression of BCRP mRNA in several lung cancer cell lines (in vitro) and lung and colorectal cancers resected on operation (in vivo).
As a cohort study, an association of methylation status of the promoter region of BCRP using MSP for biopsy specimens of lung cancer patients before chemotherapy with the responsibility for anticancer drugs was examined. This DNA-based diagnosis revealed that the sensitivity was 83.3% and the specificity was 77.8%. This study implies that it is very useful as a new biomarker in predicting drug resistance and responsibility for anticancer drugs to examine methylation status of the promoter region of BCRP using MSP for not only lung cancers, but also colorectal cancers, gastric cancers, breast cancers, ovarian tumors, and choriocarcinomas. Less
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[Book] 肺癌の外来科学療法2005
Author(s)
山口博之, 早田 宏, 他
Total Pages
304-309
Publisher
成人病と生活習慣病35(3)
Description
「研究成果報告書概要(和文)」より
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