Novel Mutation of Topoisomerase I in Rendering Cells Resistant to Camptothecin

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 藥學院 > 藥學系暨碩博士班 > 期刊論文 > Item 310903500/7692

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題名:	Novel Mutation of Topoisomerase I in Rendering Cells Resistant to Camptothecin
作者:	(Chang, J.-Y.);(Liu, J.-F.);莊聲宏(Shin-Hun Juang);(Liu T.-W.);(Chen, L.-T)
貢獻者:	藥學院藥學系;中國附醫醫學研究部細胞及基因治療研究室
日期:	2002-07
上傳時間:	2009-08-26 16:33:58 (UTC+8)
摘要:	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) I catalytic activity of CPT30 and CPT30R cells was 30% and 200%, respectively, compared with that of HONE-1 cells. The expression of Top I 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 I 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 I of both CPT30 and CPT30R cells. Wild-type Top I 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 I were responsible for CPT resistance in CPT30 cells. CPT resistance in CPT30R cells was caused by mutation of Top I.
關聯:	CANCER RESEARCH 62(13)3716 ~3721
顯示於類別:	[藥學系暨碩博士班] 期刊論文

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