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Title: The antiproliferative effects of somatostatin
Author: Alderton, F.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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Somatostatin (SRIF) exerts its antiproliferative actions through membrane bound receptors, for which there are currently five distinct receptor genes cloned (sst1.5). The main objectives of this study were to (a) characterise the effects of activation of the SIRF1 group of receptors (namely the sst2, sst3 and sst5 receptors) on cell proliferation on CHO-K1 cells, and (b) investigate the possible involvement of particular intracellular signalling molecules in the antiproliferative effect of somatostatin through human somatostatin receptors. The pharmacology of the clinically used somatostatin analogue, angiopeptin (BIM-23014; sst2/sst3 selective), was examined throughout the course of this study. Somatostatin did not modulate basal proliferation of CHO-K1 cells selectively expressing human somatostatin SRIF1 receptors. Further experiments using rat recombinant somatostatin receptors illustrated species differences with angiopeptin comparatively more efficacious at rat receptors. The major conclusions from this study are (a) species differences may explain the poor clinical benefit reported for angiopeptin in the treatment of restenosis in view of initial encouraging animal data, (b) the intrinsic activity and potency estimates for angiopeptin at an individual receptor type changed dramatically depending on the functional response measured, and (c) the antiproliferative effect of somatostatin through the human sst2 and sst5 receptors is mediated via a sustained stimulation of MAP kinase resulting in increased expression of p21. Both the duration and the strength of MAP kinase activation appears to be crucial to the resultant effects on cell growth. These findings have important implications for understanding agonist activity and the use of animal models for predicting clinical utility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available