| Co-Investigator(Kenkyū-buntansha) |
KAWAMOTO Toshihiro University of Occupational and Environmental Health, Japan, School of Medicine, Professor, 医学部, 教授 (60177748)
SUGIO Kenji University of Occupational and Environmental Health, Japan, School of Medicine, Associate professor, 医学部, 助教授 (70235927)
ISSE Toyohi University of Occupational and Environmental Health, Japan, School of Medicine, Assistant professor, 医学部, 講師 (80341494)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
[Introduction] The cytochrome P450 (CYP) is associated with tumor development and progression as well as activation of anti-cancer prodrugs and their metabolic clearance. Recently, some CYPs, in particular enzymes of the CYP3A subfamily (CYP3A4, CYP3A5, and CYP3A7), have been found to play a role in the metabolism of many anticancer drugs. CYP3A not only inactivates major anticancer drugs, such as tamoxifen, taxol and vinca alkaloids, but also activates major anticancer prodrugs, such as cyclophosphamide and ifosphamide. For the better management of lung cancer, it is essential to understand the roles of CYPs and the relationships between their expression and the clinical feature of individual lung cancers. In this study, we investigate the expression of four CYPs (CYP1A1, CYP2A6, CYP2E1 and CYP3A) in 78 non-small cell lung cancer (NSCLC) and their relationships to each other, tumor p53 expression, and clinical features of the patients.
[Materials and Methods] We examined CYPs and p53 i
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mmunoreactivities in 78 Japanese patients with NSCLC who underwent surgical resection at UOEH after obtaining appropriate informed consent. Histological typing of the tumors was performed according to the WHO classification (adenocarcinoma ; 48 cases, squamous cell carcinoma ; 30 cases). Immunohistochemical staining (IHC) of 78 NSCLC was performed by the LSAB (labelled streptavidine biotin) method. CYPs and p53 expression was determined as positive when more than 10% of tumor cells were stained. The p53 mutations in 48 adenocarcinomas were sequenced by the dideoxy chain termination method using an ABI 373A DNA Sequencer (Applied Biosystems).
[Results] The CYP1A1, CYP2A6, CYP2E1 and CYP3A positive rates in 48 adenocarcinomas were 43.8% (21/48), 45.8% (22/48), 39.6% (19/48) and 39.6% (19/48), respectively, although there was no CYPs positive cases in 30 squamous cell carcinomas. The CYPs positive rates in female adenocarcinoma were higher than those in male adenocarcinoma. The CYPs positive rates in early adenocarcinoma were higher than those in advanced adenocarcinoma. The CYPs positive rates in well and moderately differentiated adenocarcinoma were higher than those in poorly differentiated adenocarcinoma. There were positive relationships among CYP1A1, CYP2E1 and Cyp3A expressions in adenocarcinoma. The CYPs expression in adenocarcinoma was independent of tumor p53 alterations.
[Conclusions] Our results suggest that better understanding of CYP expression in tumors should be useful and essential, 1) to investigate the mechanism of carcinogenesis, 2) to apply CYP expression as tumor marker, 3) to use the knowledge of CYP expression for molecular targeting therapy, 4) for selection of anti-cancer drug. Less
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