Future aspects of somatostatin-receptor-mediated therapy.

More than 30 years have passed since somatostatin was discovered and its hormonal function defined. The wide range of anatomical distribution and actions of somatostatin and its receptors have stimulated intense scientific and clinical interest. The development of somatostatin analogues helped define its usefulness in the treatment of endocrine diseases and cancer. The molecular cloning of five distinct subtypes of somatostatin receptors in the 1980s has significantly increased our insight into the biology of somatostatin and its receptor subtypes and has led to the design and development of subtype-selective peptides and nonpeptide agonists and antagonists. In the future, the development of somatostatin-receptor-mediated treatment will go along different lines. Tumor-targeted radioactive treatment based on somatostatin analogues will be further developed and improved. New somatostatin analogues will come into clinical practice, both receptor subtype-specific analogues, but also pan-receptor analogues. One is currently in clinical trial--SOM230--which is a cyclo-hexapeptide binding with high affinity to receptor type 1, 2, 3 and 5, but not 4. It has already shown activity both in acromegaly and in neuroendocrine gastrointestinal tumors. Preclinical studies on somatostatin analogues, coupled to cytotoxic agents, have shown rather promising results and will hopefully be further developed in clinical trials. Another interesting area is treatment of neuroendocrine gut tumors with ultra-high doses of somatostatin analogues, which has demonstrated significant clinical effects in patients resistant to standard-dose treatment with the same somatostatin analogue.