The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues.
The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues.
复制标题
DOI：
10.1038/bjc.1997.227
复制
发表时间：
1997
影响因子：
8.8
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Turley, H;Comley, M;Houlbrook, S;Nozaki, N;Kikuchi, A;Hickson, ID;Gatter, K;Harris, AL
在哺乳动物细胞中，DNA拓扑异构酶II有两种异构体，分别是α （170-kDa形式）和β （180-kDa形式）。先前对细胞系的研究表明，拓扑异构酶i α和β异构体在细胞周期和生长状态的变化中受到不同的调节。此外，这两种异构体都可以作为一系列抗肿瘤药物的靶点。在这里，我们分析了在人类正常组织分布的拓扑异构酶ⅱα和β使用异构体特异性抗体。此外，我们还研究了69例原发性肿瘤活检中这些同型异构体的表达，这些肿瘤代表了对拓扑异构酶ii靶向药物有反应的肿瘤（乳腺癌、肺癌、淋巴瘤和精原细胞瘤）或表现出新生耐药性的肿瘤（结肠癌）。拓扑异构酶iα仅在所有正常组织的增殖室中表达，在细胞核和细胞质中均可检测到。在生物侵袭性或快速增殖的肿瘤（如高级别淋巴瘤和精原细胞瘤）中，存在高水平的拓扑异构酶iα，尽管在结肠肿瘤中仍可检测到其表达，这表明该异构体的表达不足以解释结肠肿瘤的内在耐药性。拓扑异构酶ii在体内普遍表达，并定位于核仁和核质中。这种异构体存在于静止细胞群中，但在所有肿瘤和增殖细胞中的表达水平普遍高于正常静止组织。我们得出结论，拓扑异构酶iiα是体内正常细胞和肿瘤细胞的严格增殖标志物，但拓扑异构酶iiα在细胞和组织中的分布比拓扑异构酶iiα更普遍。肿瘤细胞中拓扑异构酶ii β的明显上调可能影响患者对包括拓扑异构酶ii靶向药物在内的抗肿瘤治疗的反应。
In mammalian cells, there are two isoforms of DNA topoisomerase II, designated alpha (170-kDa form) and beta (180-kDa form). Previous studies using cell lines have shown that the topoisomerase IIalpha and beta isoforms are differentially regulated during the cell cycle and in response to changes in growth state. Moreover, both isoforms can act as targets for a range of anti-tumour drugs. Here, we have analysed the normal tissue distribution in humans of topoisomerase IIalpha and beta using isoform-specific antibodies. In addition, we have studied expression of these isoforms in 69 primary tumour biopsies, representative either of tumours that are responsive to topoisomerase II-targeting drugs (breast, lung, lymphoma and seminoma) or of those that show de novo drug resistance (colon). Topoisomerase IIalpha was expressed exclusively in the proliferating compartments of all normal tissues, and was detectable in both the cell nucleus and cytoplasm. In biologically aggressive or rapidly proliferating tumours (e.g. high-grade lymphomas and seminomas), there was a high level of topoisomerase IIalpha, although expression was still detectable in colon tumours, indicating that expression of this isoform is not sufficient to explain the intrinsic drug resistance of colon tumours. Topoisomerase IIbeta was expressed ubiquitously in vivo and was localized in both the nucleoli and the nucleoplasm. This isoform was present in quiescent cell populations, but was expressed at a generally higher level in all tumours and proliferating cells than in normal quiescent tissues. We conclude that topoisomerase IIalpha is a strict proliferation marker in normal and neoplastic cells in vivo, but that topoisomerase IIbeta has a much more general cell and tissue distribution than has topoisomerase IIalpha. The apparent up-regulation of topoisomerase IIbeta in neoplastic cells has implications for the response of patients to anti-tumour therapies that include topoisomerase II-targeting drugs.
登录
查看更多内容
DOI：
10.1073/pnas.85.19.7177
发表时间：
1988-10-01
影响因子：
11.1
作者：
TSAIPFLUGFELDER, M;LIU, LF;WANG, JC
通讯作者：
WANG, JC
影响因子：
3
作者：
POMMIER, Y
通讯作者：
POMMIER, Y
影响因子：
3.4
作者：
HELLEMANS, P;VANDAM, PA;VANMARCK, E
通讯作者：
VANMARCK, E
影响因子：
8.8
作者：
Houlbrook S;Addison CM;Davies SL;Carmichael J;Stratford IJ;Harris AL;Hickson ID
通讯作者：
Hickson ID
影响因子：
8.5
作者：
PROSPERI, E;NEGRI, C;RICOTTI, GCBA
通讯作者：
RICOTTI, GCBA