Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane; ADR-529] and ICRF-159 (Razoxane).
Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane; ADR-529] and ICRF-159 (Razoxane).
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在拓扑异构酶 II 抑制剂 ICRF-187 [( )-1,2-双(3,5-二氧代哌嗪基-1-基)丙烷存在下培养的哺乳动物细胞的细胞周期进展和染色体分离；
作者：
G. Gorbsky
某些双（2，6-二氧代哌嗪）衍生物，包括ICRF-187 [（+）-1，2-双（3，5-二氧代哌嗪基-1-基]丙烷; ADR-529）及其外消旋化合物ICRF 159（Razoxane），已被研究为抑制剂。此外，ICRF-187目前正在作为改善蒽环类药物治疗的心脏毒性的药物进行深入研究。这些药物最近被鉴定为拓扑异构酶II的抑制剂。我们研究了ICRF-187和ICRF-159对培养的上皮细胞通过M期的进展的影响。在药物添加后约1.5小时开始，染色体凝集被显著抑制。细胞以接近正常的速率进入并通过M期，但在后期缺乏完全的染色体分离导致对正常染色体分布的灾难性影响。免疫标记与佳洁士自身免疫血清，它承认着丝粒蛋白，并与MPM-2单克隆抗体，它承认有丝分裂磷蛋白，表明染色体的着丝粒组装一个正常的中期阵列中存在的ICRF-187和ICRF-159。分裂后期着丝粒的分离开始正常，但没有完成，因为染色单体臂未能相互脱离。大量的染色体桥形成，染色质团被困在分裂沟中，导致其不均匀地分布到子细胞中。在许多情况下，所有的染色质都被推入两个分裂细胞中的一个。基于流式细胞术的先前研究表明，双（2，6-二氧代哌嗪）衍生物引起具有4 N DNA含量的细胞的积累，这可能反映了有丝分裂中染色体的不完全分离，而不是如已经提出的细胞周期G2中的阻滞。
Certain bis(2,6-dioxopiperazine) derivatives, which include ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl]propane; ADR-529) and its racemic compound ICRF 159 (Razoxane), have been investigated as antineoplastic agents. In addition, ICRF-187 is currently under intense study as an agent to ameliorate the cardiac toxicity of anthracycline therapy. These agents have recently been identified as inhibitors of topoisomerase II. We studied the effects of ICRF-187 and ICRF-159 on the progression of cultured epithelial cells through M phase. Beginning approximately 1.5 h after drug addition, chromosome condensation was significantly inhibited. Cells entered and progressed through M phase at near normal rates, but the lack of complete chromosome separation during anaphase resulted in catastrophic effects on normal chromosome distribution. Immunolabeling with Crest autoimmune sera, which recognizes centromere proteins, and with MPM-2 monoclonal antibody, which recognizes mitotic phosphoproteins, indicated that the centromeres of the chromosomes assembled a normal metaphase array in the presence of ICRF-187 and ICRF-159. Centromere separation in anaphase was initiated normally but was not completed because the chromatid arms failed to disengage from each other. Massive chromosome bridges were formed, and the chromatin mass became trapped in the cleavage furrow leading to its unequal distribution to the daughter cells. In many cases, all the chromatin was pushed into one of the two dividing cells. It is likely that previous studies, based on flow cytometry, indicating that bis(2,6-dioxypiperazine) derivatives cause an accumulation of cells with a 4N DNA content, reflect the incomplete segregation of chromosomes in mitosis rather than a block in G2 of the cell cycle as had been proposed.
DOI：
10.1073/pnas.85.4.1086
发表时间：
1988-02-01
影响因子：
11.1
作者：
HECK, MMS;HITTELMAN, WN;EARNSHAW, WC
通讯作者：
EARNSHAW, WC
DOI：
10.1073/pnas.80.10.2926
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
DAVIS, FM;TSAO, TY;RAO, PN
通讯作者：
RAO, PN
人类原角质形成细胞中两种功能不同的生长停滞状态，可调节克隆形成潜力。
DOI：
10.1111/1523-1747.ep12285684
发表时间：
1986
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Pittelkow,MR;WilleJr,JJ;Scott,RE
通讯作者：
Scott,RE