Therapeutic and diagnostic implications of the somatostatin system in gastroenteropancreatic neuroendocrine tumour disease.
Somatostatin exerts its actions through interaction with specific heptahelical G-protein coupled plasma membrane receptors. Five different somatostatin receptor subtypes have been cloned in man. Different receptor subtypes are coupled to different intracellular transmission cascades in a cell type-dependent manner. In general, somatostatin affects cell proliferation either directly: reducing mitogen-activated protein kinase cascade, activating phosphoproteinphosphatase, stimulating EGF-receptors and adenylate cyclase activity; or indirectly reducing the release of autocrine- and/or paracrine-acting growth factors. Somatostatin can exert cytotoxic (G1 phase cell arrest) or cytostatic (apoptosis induction) effects, also depending on the receptor subtype expressed on the target cell. In gastroenteropancreatic neuroendocrine tumours predominance of sst1 and sst2 with a lesser extent of sst3 and sst5 subtype receptors have been demonstrated using sensitive methods. Synthetic analogues with specific decreasing affinity for sst2 > sst5 > sst3 receptor subtypes have been used as antiproliferative drug in the treatment of gastroenteropancreatic tumours. These compounds (octreotide, lanreotide) resulted in a modest growth-inhibition activity either in functioning or in non-functioning tumours. Combination of somatostatin analogues with alpha-interferon produced a more pronounced antiproliferative effect overcoming therapy resistance developed to either single drug. Finally, the development of radio-labelled somatostatin analogue scintigraphy has contributed to gastroenteropancreatic-tumours lesion localization and future more detailed knowledge of somatostatin receptor mechanisms could improve both the diagnostic and therapeutic application of somatostatin analogues.
Höcker
M
M
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Universitätsklinikum Charité, Humboldt Universität Berlin, Germany.
Wiedenmann
B
B
D005260:Female; D006801:Humans; D008297:Male; D018358:Neuroendocrine Tumors / Q000175:diagnosis* / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D017481:Receptors, Somatostatin / Q000008:administration & dosage / Q000502:physiology; D012680:Sensitivity and Specificity; D013004:Somatostatin / Q000378:metabolism / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000188:drug therapy
D017481:Receptors, Somatostatin; D013004:Somatostatin