APOPTOSIS IN ANTITUMOR STRATEGIES - MODULATION OF CELL-CYCLE OR DIFFERENTIATION
APOPTOSIS IN ANTITUMOR STRATEGIES - MODULATION OF CELL-CYCLE OR DIFFERENTIATION
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DOI：
10.1002/jcb.240580204
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发表时间：
1995-06-01
影响因子：
4
通讯作者：
DARZYNKIEWICZ, Z
中科院分区：
文献类型：
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作者：
DARZYNKIEWICZ, Z
有强有力的证据表明，服用抗肿瘤药物会触发靶细胞的凋亡性死亡。细胞凋亡的一个特征是受影响的细胞主动参与其死亡。因此，人们试图通过调节细胞通过凋亡作出反应的倾向来增强各种药物的细胞毒性。讨论了几种促进细胞凋亡的策略，这些策略涉及到调节细胞周期或分化。失去对肿瘤细胞G(1)检查点的控制，使人们可以设计在检查点阻止正常细胞的治疗方法，并尝试用S期特异性药物选择性地杀死肿瘤细胞。当G(1)检查点功能被取消时，肿瘤抑制基因p53的凋亡触发功能可能会恢复，这有望增加肿瘤细胞对S期毒物的敏感性。由于许多抗肿瘤药物的诱导凋亡是细胞周期特异性的，因此优先在细胞周期的不同阶段触发细胞凋亡或将细胞重新招募到敏感期的药物组合提供了另一种抗肿瘤策略。也有证据表明，当DNA损伤后触发细胞分化时，细胞凋亡会得到加强。这一观察结果表明，结合DNA损伤和区分药物的策略可能是成功的，条件是后者在前者造成DNA损伤后给药。(C)1995年Wiley-Liss公司
There is a strong evidence that administration of antitumor drugs triggers apoptotic death of target cells. A characteristic feature of apoptosis is active participation of the affected cell in its demise. Attempts have been made, therefore, to potentiate the cytotoxicity of a variety of agents by modulating the propensity of cells to respond by apoptosis. Several strategies to enhance apoptosis that involve modulation of the cell cycle or differentiation are discussed. Loss of control of the G(1) checkpoint in tumor cells allows one to design treatments that arrest normal cells at the checkpoint and attempt to selectively kill tumor cells with S phase specific drugs. The possibility of a restoration of the apoptosis triggering function of the tumor suppressor gene p53 when the G(1) checkpoint function is abolished is expected to increase tumor cells' sensitivity to S phase poisons. Because induction of apoptosis by many antitumor drugs is cell cycle phase specific, drug combinations that preferentially trigger apoptosis at different phases of the cycle, or recruitment of cells to the sensitive phase, offer another antitumor strategy. There is also evidence that apoptosis is potentiated when cell differentiation is triggered following DNA damage. This observation suggests that strategies which combine DNA damaging and differentiating drugs, under conditions where the latter are administered following DNA damage caused by the former, may be successful. (C) 1995 Wiley-Liss, Inc.