國家衛生研究院 NHRI:Item 3990099045/8578
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    題名: O6-Methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma
    作者: Chen, SH;Kuo, CC;Li, CF;Cheung, CH;Tsou, TC;Chiang, HC;Yang, YN;Chang, SL;Lin, LC;Pan, HY;Chang, KY;Chang, JY
    貢獻者: National Institute of Cancer Research;Institute of Biotechnology and Pharmaceutical Research;Division of Environmental Health and Occupational Medicine
    摘要: Cisplatin (CDDP) is an important anti-cancer drug commonly used in various human cancers, including nasopharyngeal carcinoma (NPC). How to overcome the drug resistance of CDDP provides opportunities to improve clinical outcomes of NPC. O6 -methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O6 - alkylguanine alkylating drugs. However, the underlying mechanism and clinical relevance between MGMT and CDDP remain poorly defined in NPC. In this study, we showed that MGMT-proficient cells were highly resistant to the cytotoxic effects of CDDP as compared to MGMT-deficient cells. Further studies showed that the platinum level of DNA after CDDP exposure was significantly lower in MGMT-proficient cells than in MGMT-deficient cells. Host cell reactivation assay revealed that MGMT protected NPC cells from CDDP-induced DNA damage by enhancing DNA repair capacity. Importantly, we demonstrated for the first time that MGMT protein directly bound to CDDP-induced DNA damages. Subsequently, CDDP-bound MGMT protein became ubiquitinated and was degraded through ubiquitin-mediated proteasome system. We further analyzed the relationship between MGMT expression and clinical survivals in a cohort of 83 NPC patients. NPC patients who received CDDP-based concurrent chemoradiotherapy (CCRT), with high MGMT expression level, exhibited shorter progression-free survival (PFS; P=.022) and overall survival (OS; P=.015), than patients with low MGMT expression level. Furthermore, high MGMT expression level remained to be an independent prognostic factor for worse PFS (P=.01, hazard ratio 2.23) and OS (P=.018, hazard ratio 2.14). Our findings suggest that MGMT protein is important to determine the efficacy of CDDP in NPC.
    日期: 2015-09
    關聯: International Journal of Cancer. 2015 Sep;137(6):1291-1305.
    Link to: http://dx.doi.org/10.1002/ijc.29486
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0020-7136&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000357808900010
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84936847044
    顯示於類別:[張俊彥] 期刊論文
    [張光裕] 期刊論文
    [郭靜娟] 期刊論文
    [鄒粹軍] 期刊論文
    [陳尚鴻] 期刊論文

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