Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors.
Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors.
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发表时间：
1991-09
期刊：
影响因子：
11.2
通讯作者：
R. Ishida;T. Miki;T. Narita;R. Yui;Makoto Sato;K. R. Utsumi;K. Tanabe;T. Andoh
中科院分区：
文献类型：
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作者：
R. Ishida;T. Miki;T. Narita;R. Yui;Makoto Sato;K. R. Utsumi;K. Tanabe;T. Andoh
在论文中，K。田边，Y.池上河Ishida和T. Andoh，Cancer Res.，五十一：4903-4908，1991），我们表明ICRF-154和ICRF-193（二氧代哌嗪衍生物）抑制纯化的拓扑异构酶II的活性，而不形成可裂解的DNA-蛋白质复合物。为了观察ICRF-154和ICRF-193是否原位影响细胞拓扑异构酶II，我们通过碱性沉降分析检测了这些药物对依托泊苷（VP-16）诱导的RPMI 8402细胞中拓扑异构酶II介导的DNA断裂的影响。当RPMI 8402细胞在ICRF-154或ICRF-193存在下暴露于VP-16 1 h时，VP-16诱导的DNA链断裂被两种ICRF化合物极大地抑制。与该观察结果平行，ICRF-193也逆转了VP-16诱导的生长抑制。细胞暴露于ICRF-154导致具有4C DNA含量的细胞进行性积累。尽管有丝分裂指数没有显著增加，但在暴露于ICRF-193或ICRF-154的细胞中观察到有丝分裂异常：所有有丝分裂细胞均表现出早期有丝分裂图，染色体浓缩和缠结较少。对ICRF-154最敏感的细胞周期是G2-M期。ICRF-154不影响纺锤体的形成。然而，在药物处理的细胞中观察到异常取向的纺锤体与多核细胞的出现平行。结果表明，ICRF-154和-193抑制RPMI 8402细胞中拓扑异构酶II的活性，这种作用导致细胞出现在G2和早期M期，具有较少的凝聚和缠结的染色体和具有多叶核的细胞。
In the accompanying paper (K. Tanabe, Y. Ikegami, R. Ishida, and T. Andoh, Cancer Res., 51: 4903-4908, 1991), we showed that ICRF-154 and -193, dioxopiperazine derivatives, inhibited the activity of purified topoisomerase II, without formation of a cleavable DNA-protein complex. In order to see whether ICRF-154 and ICRF-193 affect cellular topoisomerase II in situ or not, we examined the effect of these drugs on etoposide (VP-16)-induced, topoisomerase II-mediated DNA breaks in RPMI 8402 cells by alkaline sedimentation analysis. When RPMI 8402 cells were exposed to VP-16 in the presence of ICRF-154 or ICRF-193 for 1 h, VP-16-induced DNA strand breaks were greatly inhibited by both ICRF compounds. In parallel with this observation, VP-16-induced growth inhibition was also reversed by ICRF-193. Exposure of cells to ICRF-154 resulted in a progressive accumulation of cells with 4C DNA content. Although mitotic index did not significantly increase, mitotic abnormalities were seen in cells exposed to ICRF-193 or ICRF-154: all mitotic cells exhibited early mitotic figures with fewer condensed and entangled chromosomes. The most sensitive phase of the cell cycle to ICRF-154 was the G2-M. ICRF-154 did not affect the spindle formation. However, abnormally oriented spindles were observed in drug-treated cells in parallel with the appearance of multinucleated cells. The results suggest that ICRF-154 and -193 inhibit topoisomerase II activity in RPMI 8402 cells, and this effect resulted in the appearance of cells in G2 and early M phase with fewer condensed and entangled chromosomes and of cells with multilobed nuclei.