Short- and long-term effects of octreotide and SOM230 on GH, IGF-I, ACTH, corticosterone and ghrelin in rats.
SOM230 is a novel somatostatin analog which shows affinity to 4 of the 5 known somatostatin receptors (SSTR1-5). In binding experiments, SOM230 has a higher affinity to SSTR1, SSTR3 and SSTR5 and a slightly lower affinity to SSTR2 compared to octreotide. In addition, SOM230 has a >7-fold longer plasma half-life than octreotide (11 vs 1.5 h). It was suggested that SOM230 with its broader binding and activity profile compared to octreotide should have a stronger (usually inhibitory) effect on the secretion of hormones. In several animal species, SOM230 was a more potent inhibitor of GH and IGF-I than octreotide. This is in line with a strong expression of both SSTR2 and SSTR5. In the pituitary of patients with primary Cushing's disease, the SSTR5 is more frequently expressed than SSTR2. Accordingly, in rats SOM230 caused a stronger inhibition of ACTH and corticosterone secretion than octreotide. In contrast, most recent experiments showed that octreotide was more potent than SOM230 to inhibit ghrelin secretion in rats. This effect could be explained by the strong expression of SSTR2 in the rat stomach, whereas expression of SSTR3, SSTR4 and SSTR5 was poor or absent. Based on these data it can be concluded that in tissues (or tumors), where several SSTRs are expressed, SOM230 will generally have a stronger effect than octreotide. In cases where SSTR2 is the most important receptor mediating a response (e.g. ghrelin release in rats), the stronger inhibitory effect of octreotide can be explained by its higher affinity for SSTR2. In contrast to the long-lasting inhibitory effect of SOM230 on GH and IGF-I secretion, the inhibitory effects of both compounds on ghrelin show strong tachyphylaxis. These data are in line with the hypothesis that activation of the SSTR2 alone results in a rapid desensitization of the response. If, however, additional SSTR subtypes (especially SSTR5) are expressed and activated by multiligand analogs like SOM230, this might not only form the basis for a stronger response, but also the basis for a reduced tachyphylaxis.
Schmid
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HA
Novartis Institutes for BioMedical Research, Oncology Research, Basel, Switzerland. herbert.schmid@novartis.com
Silva
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AP
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D015282:Octreotide / Q000494:pharmacology*; D036361:Peptide Hormones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000187:drug effects / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013972:Thyrotropin / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D054439:Ghrelin; D036361:Peptide Hormones; D011986:Receptors, Somatotropin; D013004:Somatostatin; D013973:Thyrotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; D000324:Adrenocorticotropic Hormone; D013972:Thyrotropin; D013006:Growth Hormone; D003346:Corticotropin-Releasing Hormone; C517782:pasireotide; D015282:Octreotide; D003345:Corticosterone