APOPTOSIS - MOLECULAR MECHANISMS AND IMPLICATIONS FOR CANCER-CHEMOTHERAPY

Apoptosis, or programmed cell death, is an orderly and genetically con trolled 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 sta rts after signalling by external triggers, such as ligation to distinc t receptors or by endogenous mechanisms related to aging or to exogeno us irreversible cellular or nuclear damage. the initiation phase is fo llowed by a decision phase. During this phase transduction occurs of t he 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 directi on. The execution phase is started when the cell has arrived ata stage of no return. The nuclear DNA is cleaved into multiples of 180-200 ba sepairs, the plasma membrane integrity and the mitochondria remain ini tially intact the cell splits up into apoptotic bodies, small vesicles which enclose the nuclear and cellular remnants. Finally, the clearin g phase is arrived, when the apoptotic bodies are phagocytosed by adja cent cells and macrophages, It is thought that the pharmacodynamics of anticancer drugs consists of two distinct steps. The first step inclu des the interaction with its cellular target, which is not lethal per se. The commitment of the cell to undergo apoptosis forms the second s tep. The efficacy of anticancer drugs is determined by the ability to selectively sensitize tumor cells to apoptosis, which depends to a lar ge 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 cha llenge in pharmacological research to explore apoptosis by modulating the extrinsic and intrinsic regulators in a positive or negative direc tion in order to improve the efficacy of anticancer treatment.