Characterization of a Chinese hamster ovary cell line with acquired resistance to the bisdioxopiperazine dexrazoxane (ICRF-187) catalytic inhibitor of topoisomerase II.
Characterization of a Chinese hamster ovary cell line with acquired resistance to the bisdioxopiperazine dexrazoxane (ICRF-187) catalytic inhibitor of topoisomerase II.
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对拓扑异构酶 II 的双二氧代哌嗪右雷佐生 (ICRF-187) 催化抑制剂具有获得性抗性的中国仓鼠卵巢细胞系的表征。
DOI：
10.1016/s0006-2952(97)00013-0
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发表时间：
1997
影响因子：
5.8
通讯作者：
J. Yalowich
中科院分区：
文献类型：
--
作者：
B. Hasinoff;T. Kuschak;A. M. Creighton;C. Fattman;W. Allan;P. Thampatty;J. Yalowich
选择了对拓扑异构酶II抑制剂Dexrazoxane(ICRF-187，Zinecard®)具有高度抗性的中国仓鼠卵巢(CHO)细胞系。耐药细胞系(DZR)对Dexrazoxane持续暴露具有1500倍的抗性(IC50=2800vs1.8μM)。DZR细胞对其他双氧哌嗪(ICRF-193、ICRF-154和ICRF-186)也有交叉耐药(8-500倍)，对蒽环类药物(柔红霉素、阿霉素、表阿霉素和伊达阿比星)和依托泊苷(8.5倍)也有一定的交叉耐药(4-14倍)，但对其他不可切割的复杂拓扑异构酶II抑制剂苏拉明和美巴龙没有交叉耐药。在膜激活剂维拉帕米存在的情况下，右旋氮杂环己烷对这两种细胞的细胞毒性没有变化。DZR细胞对Dexrazoxane介导的拓扑异构酶IIDNA降解活性的抑制作用是CHO细胞的9倍(IC50=400vs45μM)，而对依托泊苷的抗性仅为CHO细胞的1.4倍(IC50=110vs83μM)。DZR细胞的拓扑异构酶II蛋白含量是亲本CHO细胞的一半。然而，使用核抽提物拓扑异构酶II的比活力没有变化。依托泊苷(100μM)诱导的DZR细胞和离体核中的拓扑异构酶II-DNA复合体的水平类似于CHO细胞和离体核中的一半。然而，在DZR细胞和细胞核中，500μM右旋氮杂环己烷抑制依托泊苷(100μM)诱导的拓扑异构酶II-DNA共价复合体的能力都比CHO细胞和细胞核降低了4-6倍。相反，与DZR细胞和分离的细胞核相比，阿克拉阿霉素或美巴隆对依托泊苷诱导的CHO中拓扑异构酶II-DNA复合体的抑制能力没有差别。结论：DZR细胞对右旋氮杂环己烷的抗药性主要是通过拓扑异构酶II靶点的改变而获得的。
A Chinese hamster ovary (CHO) cell line highly resistant to the non-cleavable complex-forming topoisomerase II inhibitor dexrazoxane (ICRF-187, Zinecard®) was selected. The resistant cell line (DZR) was 1500-fold resistant (IC50= 2800 vs 1.8 μM) to continuous dexrazoxane exposure. DZR cells were also cross-resistant (8- to 500-fold) to other bisdioxopiperazines (ICRF-193, ICRF-154, and ICRF-186), and somewhat cross-resistant (4- to 14-fold) to anthracyclines (daunorubicin, doxorubicin, epirubicin, and idarubicin) and etoposide (8.5-fold), but not to the other non-cleavable complex-forming topoisomerase II inhibitors suramin and merbarone. The cytotoxicity of dexrazoxane to both cell lines was unchanged in the presence of the membrane-active agent verapamil. DZR cells were 9-fold resistant to dexrazoxane-mediated inhibition of topoisomerase II DNA decatenation activity compared with CHO cells (IC50= 400 vs 45 μM), but were only 1.4-fold (IC50= 110 vs 83 μM) resistant to etoposide. DZR cells contained one-half the level of topoisomerase II protein compared with parental CHO cells. However, the specific activity for decatenation using nuclear extract topoisomerase II was unchanged. Etoposide (100 μM)-induced topoisomerase II-DNA complexes in DZR cells and isolated nuclei were similarly one-half the level found in CHO cells and in isolated nuclei. However, the ability of 500 μM dexrazoxane to inhibit etoposide (100 μM)-induced topoisomerase II-DNA covalent complexes was reduced 4- to 6-fold in both DZR cells and nuclei compared with CHO cells and nuclei. In contrast, there was no differential ability of aclarubicin or merbarone to inhibit etoposide-induced topoisomerase II-DNA complexes in CHO compared with DZR cells and isolated nuclei. It was concluded that the DZR cell line acquired its resistance to dexrazoxane mainly through an alteration in the topoisomerase II target.
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DOI：
10.1016/s1054-3589(08)61136-9
发表时间：
1994
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
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DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Wasserman,RA;Wang,JC
通讯作者：
Wang,JC
影响因子：
11.2
作者：
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通讯作者：
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DOI：
--
发表时间：
1996
期刊：
Molecular pharmacology.
影响因子：
--
作者：
Ganapathi,R;Constantinou,A;Kamath,N;Dubyak,G;Grabowski,D;Krivacic,K
通讯作者：
Krivacic,K
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DOI：
--
发表时间：
1995
期刊：
Cancer research.
影响因子：
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作者：
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通讯作者：
Andoh,T