Guchelaar H J, Vermes A, Vermes I, Haanen C
Department of Clinical Pharmacy, Academic Medical Center, University of Amsterdam, The Netherlands.
Pharm World Sci. 1997 Jun;19(3):119-25. doi: 10.1023/a:1008654316572.
Apoptosis, or programmed cell death, is an orderly and genetically controlled form of cell death. In a morphological sense, it differs from necrosis in that cellular shrinkage and chromatin condensation occurs, followed by fragmentation of nuclear components within membrane-bound vesicles which are cleared by phagocytosis without damage to adjacent tissue. The molecular pathway includes an initiating phase, which starts after signalling by external triggers, such as ligation to distinct receptors or by endogenous mechanisms related to aging or to exogenous irreversible cellular or nuclear damage. The initiation phase is followed by a decision phase. During this phase transduction occurs of the apoptotic signal to nuclear and cytoplasmatic target enzymes, which includes activation of endonucleases and enzymatic alterations of the cytoskeleton. There are numerous proteins and lipid-derived moieties which modulate the apoptotic mechanism in positive or negative direction. The execution phase is started when the cell has arrived at a stage of no return. The nuclear DNA is cleaved into multiples of 180-200 basepairs, the plasma membrane integrity and the mitochondria remain initially intact, the cell splits up into apoptotic bodies, small vesicles which enclose the nuclear and cellular remnants. Finally, the clearing phase is arrived, when the apoptotic bodies are phagocytosed by adjacent cells and macrophages. It is thought that the pharmacodynamics of anticancer drugs consists of two distinct steps. The first step includes the interaction with its cellular target; which is not lethal per se. The commitment of the cell to undergo apoptosis forms the second step. The efficacy of anticancer drugs is determined by the ability to selectively sensitize tumor cells to apoptosis, which depends to a large extent from the expression of various oncogenes, such as bcl-2, p53, bax, ras, c-myc and others, and from endogenous factors. It is a challenge in pharmacological research to explore apoptosis by modulating the extrinsic and intrinsic regulators in a positive or negative direction in order to improve the efficacy of anticancer treatment.
细胞凋亡，即程序性细胞死亡，是一种有序且受基因控制的细胞死亡形式。从形态学角度来看，它与坏死不同，细胞凋亡会发生细胞皱缩和染色质浓缩，随后核成分在膜结合小泡内碎片化，这些小泡通过吞噬作用被清除，而不会对相邻组织造成损伤。分子途径包括起始阶段，该阶段在外部触发信号后启动，例如与特定受体结合或通过与衰老相关的内源性机制，或由外源性不可逆的细胞或核损伤引发。起始阶段之后是决定阶段。在此阶段，凋亡信号转导至细胞核和细胞质中的靶酶，这包括核酸内切酶的激活以及细胞骨架的酶促改变。有许多蛋白质和脂质衍生部分可正向或负向调节凋亡机制。当细胞到达不可逆转的阶段时，执行阶段开始。核DNA被切割成180 - 200碱基对的倍数，质膜完整性和线粒体最初保持完整，细胞分裂成凋亡小体，即包裹着核和细胞残余物的小泡。最后，当凋亡小体被相邻细胞和巨噬细胞吞噬时，清除阶段到来。据认为，抗癌药物的药效学包括两个不同的步骤。第一步包括与其细胞靶点相互作用；这本身并不致命。细胞进入凋亡的过程构成第二步。抗癌药物的疗效取决于其选择性使肿瘤细胞对凋亡敏感的能力，这在很大程度上取决于各种癌基因的表达，如bcl - 2、p53、bax、ras、c - myc等，以及内源性因素。在药理学研究中，通过正向或负向调节外在和内在调节因子来探索细胞凋亡，以提高抗癌治疗的疗效，这是一项挑战。
