國家衛生研究院 NHRI:Item 3990099045/2838
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/2838


    Title: Novel mutation of topoisomerase I in rendering cells resistant to camptothecin
    Authors: Chang, JY;Liu, JF;Juang, SH;Liu, TW;Chen, LT
    Contributors: National Institute of Cancer Research
    Abstract: To identify mechanisms of camptothecin (CPT) resistance and the relationship between CPT-resistant cells and other anticancer agents, a CPT-resistant cell line (CPT30) and its partial revertant cell line (CPT30R) were established from a human nasopharyngeal carcinoma cell line (HONE-1). CPT30 and CPT30R cells displayed a 14- and 3.5-fold resistance to CPT compared with HONE-1 cells, respectively. The resistant and partial revertant cell lines showed cross-resistance to topotecan and increased sensitivity to cisplatin, carboplatin, and 1,3-bis(chloroethyl)-1-nitrosurea. The topoisomerase (Top) 1 catalytic activity of CPT30 and CPT30R cells was 30% and 200%, respectively, compared with that of HONE-1 cells. The expression of Top 1 protein and mRNA levels in CPT30 cells was 40% and 30% less than that in HONE-1 cells, respectively, whereas in CPT30R cells, the levels of Top 1 protein and mRNA were 50% and 20% higher, respectively, than that in HONE-1 cells. Both the resistant and revertant cell line whole-cell lysates demonstrated different levels of sensitivity to CPT in in vitro assays in comparison with that of HONE-1 cells. Furthermore, CPT exhibited 15- and 7-fold better binding affinity in stabilizing protein-linked DNA breaks in HONE-1 cells than in CPT30 and CPT30R cells, respectively. Direct DNA sequencing of the reverse transcription-PCR product and genomic DNA revealed a point mutation resulting in E418K mutation in the Top 1 of both CPT30 and CPT30R cells. Wild-type Top 1 RNA and genomic DNA were also detected in these two cell lines. A yeast system was used to examine whether this mutation could be responsible for CPT resistance. Our results showed that a single amino acid change (E418K) resulted in CPT resistance. Therefore, quantitative and qualitative changes in Top 1 were responsible for CPT resistance in CPT30 cells. CPT resistance in CPT30R cells was caused by mutation of Top 1.
    Keywords: Oncology
    Date: 2002-07-01
    Relation: Cancer Research. 2002 Jul;62(13):3716-3721.
    Link to: http://cancerres.aacrjournals.org/cgi/content/abstract/62/13/3716
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000176579500026
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0036644899
    Appears in Collections:[Li-Tzong Chen] Periodical Articles
    [Tsang-Wu Liu] Periodical Articles
    [Jang-Yang Chang] Periodical Articles
    [Shin-Hun P. Juang(1997-2004)] Periodical Articles

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