Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it is estimated that approximately 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002 and hence oncology remains a major pharmaceutical area (see "Cancer Treatment 2002" a full analysis of current and future pharmaceutical approaches to cancer). Recent trends have included the development of strategies to promote apoptosis and as this field matures indication other than cancer are being investigated. For example molecules able to stimulate apoptosis are now emerging as treatments of rheumatoid arthritis. This disease is dominated by the presence of macrophages, lymphocytes and synovial fibroblasts, which leads to the destruction of bone and cartilage. A reduced rate of macrophage apoptosis has been identified as both an etiological factor and a possible therapeutic target of this condition. Since rheumatoid arthritis causes long-term suffering to about 1% of all populations, implicating apoptosis in this disease will significantly increase the therapeutic and commercial potential of apoptosis agonists. On the other hand inhibitors of apoptosis are also gaining attention, particularly with respect to the treatment of stroke. About half as frequent as cancer, ischemic stroke affects about 600,000 Americans each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke are therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only thrombolysis is approved as a treatment strategy, and for only a brief window of time. Since many patients present far beyond this three-hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of new opportunities including the identification of molecules able to block apoptosis. In the "Target of the month" section of this edition of TherapeuticAdvances we highlight the potential of STAT5. Signal transducers and activators of transcription (STATs) are proteins that, as their name suggests, serve the dual function of signal transduction and activators of transcription in cells exposed to signaling polypeptides. This family now includes STAT1, STAT2, STAT3, STAT4, STAT5 (A and B) and STAT6. Over 30 different polypeptides have been identified as being able to activate the Stat family in various mammalian cells and the various STATs have now been implicated in a number of diseases. Recent studies indicate a role for STATs in apoptosis. Depending upon the particular stimulus or cell type, STATs can mediate either pro-apoptotic signals or anti-apoptotic signals. STAT1 and, under some circumstances STAT3 are important for transducing pro-apoptotic signals whereas STAT3 and STAT5 have been implicated in promoting cell survival. Recent studies demonstrate that regulation of apoptotic pathways by STATs is largely due to transcriptional activation of genes that encode proteins that mediate or trigger the cell death process, such as Bcl-xL, caspases, Fas and TRAIL as well as those that regulate cell cycle progression, such as p21waf1. Interestingly, STAT proteins may also regulate apoptosis through a non-transcriptional mechanism by inhibiting the anti-apoptotic protein NF-kappaB. Considering that dysregulation of the STAT signaling pathway is commonly found in clinical tumor samples, understanding the mechanisms underlying STAT regulation of cell survival may lead to successful strategies for targeting STATs in cancer therapy.

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