ANALYSIS OF EVENTS ASSOCIATED WITH CELL-CYCLE ARREST AT G2 PHASE AND CELL-DEATH INDUCED BY CISPLATIN
ANALYSIS OF EVENTS ASSOCIATED WITH CELL-CYCLE ARREST AT G2 PHASE AND CELL-DEATH INDUCED BY CISPLATIN
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DOI：
10.1093/jnci/82.9.749
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发表时间：
1990-05-02
影响因子：
10.3
通讯作者：
EASTMAN, A
中科院分区：
文献类型：
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作者：
SORENSON, CM;BARRY, MA;EASTMAN, A
DNA是顺铂的公认靶点，但最近的证据表明，DNA合成是关键过程。L1210/0细胞与顺铂孵育2小时后进入细胞周期的G2期，并在此停滞数天。然后，它们要么在细胞周期中进步，要么死亡。在最终死亡的细胞中，总转录、多腺苷化[PolyA+]RNA合成和蛋白质合成仅在48小时后才明显受到抑制。烟酰胺腺嘌呤二核苷酸(NAD)和三磷酸腺苷(ATP)水平在3天后下降。4d后细胞膜失去完整性。这些结果表明，细胞可以受到致命的损害，但在几天内仍能继续进行明显的正常代谢活动。在先前的研究中，DNA双链断裂在1天后被检测到。我们现在发现，在2天后，在染色质的核小体间隔区可以看到断裂。这种类型的损伤与通过细胞凋亡过程发生的细胞死亡是一致的。细胞萎缩和形态也与这种类型的细胞死亡相一致。这里报告的缓慢细胞死亡似乎发生在G2/M过渡阶段，可能涉及通常发生在细胞周期的这个阶段的事件。这些结果证明了DNA降解作为细胞死亡的早期和可能的关键步骤的重要性。
DNA is the accepted target for cisplatin, but recent evidence has shed doubt on DNA synthesis as the critical process. L1210/0 cells incubated for 2 hours with cisplatin progress to the G2 phase of the cell cycle and are arrested there for several days. They then either progress in the cell cycle or die. In cells that eventually die, total transcription, polyadenylated [poly(A)+]RNA synthesis, and protein synthesis were markedly inhibited only after 48 hours. Nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP) levels decreased after 3 days. Cell membrane integrity was lost after 4 days. These results demonstrate that cells can be lethally damaged, yet continue to undergo apparently normal metabolic activities for several days. In a previous study, DNA double-strand breaks were detected after 1 day. We now show that by 2 days, breaks are visible as fragmentation in the nucleosome spacer regions of chromatin. This type of damage is consistent with cell death occurring by the process of apoptosis. Cell shrinkage and morphology were also consistent with this type of cell death. The slow cell death reported here appears to occur at the G2/M transition and may involve events that normally occur at this stage of the cell cycle. These results demonstrate the importance of DNA degradation as an early and possibly essential step in cell death.