Apoptosis regulating proteins as targets of therapy for haematological malignancies

Most chemotherapeutic agents used in the treatment of haematological malignancies cause cell death by inducing apoptosis through undefined means. The discovery of the proteins involved in apoptosis and the description of apoptotic pathways suggest new potential targets for therapeutic intervention. Both 'intrinsic' and 'extrinsic' pathways can be activated separately, but activation of caspases appears central to most apoptotic pathways. Novel approaches attempt to induce apoptosis by directly targeting a portion of an apoptotic pathway. Agents that trigger signalling of Fas or tumour necrosis factor- (TNF-) related apoptosis inducing ligand (TRAIL) receptor seek to induce the extrinsic pathway at the cell surface. The BCL-2 family of proteins seems central to the regulation of those apoptotic pathways that involve mitochondrial sequestration or the release of cytochrome c, with subsequent activation of Apaf-1, caspase-9 and caspase-3. The activity of this family may depend upon both the phosphorylation state of different members and the relative level of pro- and anti-apoptotic members. New agents such as the staurosporine analogue UCN-01 and bryostatin are thought to affect apoptosis induction by altering BCL-2 phosphorylation. Others, such as BCL-2 antisense and ATRA attempt to modulate the protein levels to promote apoptosis. Direct activation of caspase-3 is a probable target, but as yet no agent with this direct function is in trial. Clinical trials of several agents have been completed or are underway. It is likely that agents that target particular points in apoptosis pathways will have antileukaemia/lymphoma activity, however, the optimal utilisation may involve combination with other more conventional agents that also activate apoptosis.