Apoptosis and cancer chemotherapy.
Apoptosis is a fundamental mechanism of cell death that can be engaged by a range of cellular insults. One of the major modes of action of chemotherapeutic drugs may be via the activation of apoptosis. Understanding how the cell death program is engaged following an insult, and hence why it fails to be engaged in certain settings, offers a novel approach to overcoming the clinical problem of drug resistance. The tumour suppressor gene p53 and its downstream effector genes p21, mdm-2, and gadd45 seem to be important in the cellular response to genotoxic drug induced damage. Considerable evidence has accrued about the effect of mutations of this pathway on drug sensitivity and this is discussed. The expanding Bcl-2 family of proteins also play an important role in the cell death program. Evidence suggests that these proteins may function as integrators of damage signals, and may be the final decision point as to whether a cell lives or dies. These proteins may thus represent a logical target for new approaches to overcoming drug resistance.
Makin
G
G
CRC Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK. guy.makin@man.ac.uk
Hickman
J A
JA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor