Somatostatin receptors and disease:Role of receptor subtypes

A variety of human neuroendocrine tumours express SSTR. The five recently cloned human SSTR subtypes have a distinct chromosomal localization and pharmacological profile, and a tissue-specific expression pattern which suggests a differential function of SSTR subtypes in different organ systems. Most tumours carrying SSTR may express multiple SSTR subtypes, while the SSTR2 subtype is most predominantly expressed. The somatostatin analogue, octreotide, binds with high affinity to the SSTR2 and SSTR5 subtype and with a low affinity to the SSTR3 subtype. This analogue does not bind to the SSTR1 and SSTR4 subtypes. No major differences in the binding characteristics have been found between octreotide and two other clinically used octapeptide SST-analogues, BIM-23014 and RC-160. Our preliminary data indicate that an absent hormonal response to octreotide in vitro also implies an absent response to BIM-23014 and RC-160. The expression of the SSTR2 subtype in human tumours is proposed to be related to a clinical beneficial effect of octreotide treatment, while the functional significance of the other SSTR subtypes is not clear at present. In addition it is unclear which subtype(s) is involved in the antimitotic actions of SST(-analogues). Further developments with regard to the oncological application of SST analogues await the identification of the SSTR subtype(s) mediating anti-proliferative effects, as well as the development of analogues which selectively activate this subtype(s). A good correlation has been found between the presence of SSTR2 subtype mRNA and binding of [125I-Tyr3]octreotide in human primary tumours. Therefore, SSTR scintigraphy of human primary tumours and their metastases presumably visualizes SSTR2-expressing tumours, although it is reasonable to assume that SSTR5, and to a lesser extent SSTR3, when expressed simultaneously with SSTR2, also contribute to the visualization of tumours.</p

Somatostatin receptors and disease:Role of receptor subtypes

A variety of human neuroendocrine tumours express SSTR. The five recently cloned human SSTR subtypes have a distinct chromosomal localization and pharmacological profile, and a tissue-specific expression pattern which suggests a differential function of SSTR subtypes in different organ systems. Most tumours carrying SSTR may express multiple SSTR subtypes, while the SSTR2 subtype is most predominantly expressed. The somatostatin analogue, octreotide, binds with high affinity to the SSTR2 and SSTR5 subtype and with a low affinity to the SSTR3 subtype. This analogue does not bind to the SSTR1 and SSTR4 subtypes. No major differences in the binding characteristics have been found between octreotide and two other clinically used octapeptide SST-analogues, BIM-23014 and RC-160. Our preliminary data indicate that an absent hormonal response to octreotide in vitro also implies an absent response to BIM-23014 and RC-160. The expression of the SSTR2 subtype in human tumours is proposed to be related to a clinical beneficial effect of octreotide treatment, while the functional significance of the other SSTR subtypes is not clear at present. In addition it is unclear which subtype(s) is involved in the antimitotic actions of SST(-analogues). Further developments with regard to the oncological application of SST analogues await the identification of the SSTR subtype(s) mediating anti-proliferative effects, as well as the development of analogues which selectively activate this subtype(s). A good correlation has been found between the presence of SSTR2 subtype mRNA and binding of [125I-Tyr3]octreotide in human primary tumours. Therefore, SSTR scintigraphy of human primary tumours and their metastases presumably visualizes SSTR2-expressing tumours, although it is reasonable to assume that SSTR5, and to a lesser extent SSTR3, when expressed simultaneously with SSTR2, also contribute to the visualization of tumours.</p

Imaging of pituitary tumours

In the neuroradiological study of pituitary tumours, second generation CT, dynamic CT and MRI provide information about the extent of the tumour and its anatomical relations with the surrounding tissues. Sometimes these techniques can distinguish primary anterior pituitary lesions from primary parasellar lesions with presentations in the sellar region. In general, contrast-enhanced MRI and dynamic CT are more sensitive than conventional CT for the diagnosis of pituitary microadenomas, as well as for the precise delineation of the parasellar invasion of macroadenomas. Radiological techniques usually cannot distinguish clinically non-functioning from functioning pituitary adenomas. BSIPSS is used for confirmation of the diagnosis of Cushing's disease as well as for the lateralization of pituitary microadenomas in Cushing's disease and some other anterior pituitary hyperfunctional states

Imaging of pituitary tumours

In the neuroradiological study of pituitary tumours, second generation CT, dynamic CT and MRI provide information about the extent of the tumour and its anatomical relations with the surrounding tissues. Sometimes these techniques can distinguish primary anterior pituitary lesions from primary parasellar lesions with presentations in the sellar region. In general, contrast-enhanced MRI and dynamic CT are more sensitive than conventional CT for the diagnosis of pituitary microadenomas, as well as for the precise delineation of the parasellar invasion of macroadenomas. Radiological techniques usually cannot distinguish clinically non-functioning from functioning pituitary adenomas. BSIPSS is used for confirmation of the diagnosis of Cushing's disease as well as for the lateralization of pituitary microadenomas in Cushing's disease and some other anterior pituitary hyperfunctional states

The interrelationship between the effects of insulin-like growth factor i and somatostatin on growth hormone secretion by normal rat pituitary cells:The role of glucocorticoids

Both insulin-like growth factor I (IGF-I) and somatostatin (SRIH) have been shown to directly inhibit GH release and the total GH content of cultured pituitary cells. In the present study we evaluated the interrelationship between the effects of a recombinant human IGF-I analog ([Thr59]IGFI) and SRIH on GH release by cultured normal rat pituitary cells together with the effects of glucocorticoids.In all experiments anterior pituitary cells were preincubated for 24 h without or with IGF-I, SRIH, and/or dexamethasone. Thereafter, 24-h incubations without or with IGF-I, dexamethasone, SRIH, and GHRH were performed. Both IGF-I and SRIH inhibited basal and GHRH-stimulated GH release in a dosedependent manner; the maximal inhibitory concentrations were 5 nM IGF-I and 10 nM SRIH. These concentrations inhibited basal and GHRH-stimulated GH release by 23μ and 40μ (IGFI) and 80μ and 85μ (SRIH), respectively.The combination of IGF-I and low concentrations of SRIH exerted an additive inhibitory effect on GHRH-stimulated GH release; IGF-I (1 nM) and SRIH (10 pM) together inhibited GH release by 50μ, while the maximal inhibitory concentrations of 5 nM IGF-I and 10 nM SRIH virtually completely inhibited GH release (by 93μ). Preincubation with 5 and 100 nM dexamethasone attenuated the sensitivity of somatotrophs to SRIH and completely abolished the inhibitory effects of IGF-I. This effect of dexamethasone could be reversed by coincubation with the glucocorticoid receptor antagonist RU 38486. High concentrations of 5†10 nM of the recombinant human IGF-I analog stimulated PRL cell content (5 and 10 nM) and release (10 nM), while a purified IGF-I preparation extracted from human blood exerted a parallel inhibitory effect on GH and PRL release.We conclude that 1) IGF-I and SRIH exert an additive direct inhibitory effect on basal and GHRH-stimulated GH secretion by normal cultured pituitary cells; 2) glucocorticoids directly attenuate the sensitivity of somatotrophs to SRIH, but completely prevent the inhibitory effects of IGF-I on GH secretion; and 3) in contrast to a purified IGF-I preparation extracted from human blood (which inhibits GH and PRL release) high concentrations of the recombinant IGF-I preparation (which inhibit GH release) stimulate PRL production.</p

Differences inthe interaction between dopamine and estradiol onprolactin release bycultured normal and tumorous human pituitary cells

Westudied the interaction between dopamine and estradiol onPRL release bycultured normal and tumorous PRL-secreting cells prepared from human pituitaries. If pituitary glands were obtained within 3 h after sudden death of previously normal individuals, theviability of isolated pituitary cells prepared by dispersion with dispase was more than75%. After 4days ofcultur, dopamine (500 nM) inhibited PRL release by cells prepared from four normal pituitaries by 24±3%(±SEM). Pretreatment of the cells with 100 nM estradiol did not alter dopamine-mediated inhibition of PRL release. Estradiol alone increased basal PRL release andcell PRL content.Cultured PRL-secreting pituitary tumor cells, obtained by transsphenoidal operation from four patients, were similarly sensitive to dopamine. Estradiol stimulated tumor cell PRL releaseand content, but significantly diminished the inhibitory effect of dopamine. Theestrogen receptor blocker tamoxifen didnotalter PRL release, butitdidreverse theestradiol-induced insensitivity of the prolactinoma cells tothedopamine agonist bromocriptine. In conclusion, these invitro results indicate that estrogensdo notantagonize theeffect of dopamine on normal human PRL-secreting pituitary cells. In human pituitarytumor cells, how-ever, estradiol decreased the sensitivity of PRL release to do-pamine (agonists), andthe estrogen action canbe acutely reversed by tamoxifen.</p