Somatostatin receptor type 5 modulates somatostatin receptor type 2 regulation of adrenocorticotropin secretion

Somatostatin inhibits adrenocorticotropin (ACTH) secretion from pituitary tumor cells. To assess the contribution of somatostatin receptor subtype 5 (SST5) to somatostatin receptor subtype 2 (SST2) action in these cells, we assessed multipathway responses to novel highly monoreceptor-selective peptide agonists and multireceptor agonists, including octreotide and somatostatin-28. Octreotide and somatostatin-28 cell membrane binding affinities correlated with their respective SST2-selective peptide ligand. Although octreotide had similar inhibiting potency (picomolar) for cAMP accumulation and ACTH secretion as an SST2-selective agonist, somatostatin-28 exhibited a higher potency (femtomolar). Baseline spontaneous calcium oscillations assessed by fluorescent confocal microscopy revealed two distinct effects: SST2 activation reduced oscillations at femtomolar concentrations reflected by high inhibiting potency of averaged normalized oscillation amplitude, whereas SST5 activation induces brief oscillation pauses and increased oscillation amplitude. Octreotide exhibits an integrated effect of both receptors; however, somatostatin-28 exhibited a complex response with two separate inhibitory potencies. SST2 internalization was visualized with SST2-selective agonist at lower concentrations than for octreotide or somatostatin-28, whereas SST5 did not internalize. Using monoreceptor-selective peptide agonists, the results indicate that, in AtT-20 cells, SST5 regulates the dominant SST2 action, attenuating SST2 effects on intracellular calcium oscillation and internalization. This may explain superior somatostatin-28 potency and provides a rationale for somatostatin ligand design to treat ACTH-secreting pituitary tumors.     

Somatostatin acts through G-proteins on dopaminergic adenylate cyclase in the caudate-putamen of the rat

Somatostatin was incubated in an adenylate cyclase assay of a particulate fraction of caudateputamen tissue of the rat in order to examine the effect of the peptide on D-1 receptor coupled adenylate cyclase in vitro. Somatostatin was able to enhance cyclic AMP formation in the presence of guanylylimidodiphosphate and guanosine-triphosphate. In contrast to this, somatostatin inhibited both dopamine and forskolin-stimulated cyclic AMP accumulation. Pertussis toxin and cholera toxin also depressed forskolin-induced stimulation. Somatostatin was found to antagonize these inhibitory effects of pertussis toxin and cholera toxin. The results suggest that somatostatin acts through a stimulatory as well as an inhibitory guanine nucleotide regulatory protein subtype to affect dopaminergic adenylate cyclase activity.     

The effect of somatostatin on the production of human interferons by mononuclear cells.

Somatostatin (SMS) is a tetradecapeptide which can inhibit the secretion of a number of peptides produced by the endocrine or nervous systems. SMS 201-995 (octreotide) is a somatostatin analogue with very potent somatostatin activities. We have been investigating the effects of both SMS and octreotide on the production of human interferon (IFN). We obtained human peripheral blood mononuclear cells from normal donors and induced them to produce IFN in the presence or absence of a number of peptides possessing somatostatin activities. SMS and octreotide were shown to inhibit the secretion of INF-gamma but not IFN-alpha. Concentrations of 10(-6) M were shown to decrease yields when Concanavalin A or phytohemagglutin were used as the inducer. Higher concentrations had a progressively greater effect. No effects were observed on IFN-gamma production if interleukin 2, ionomycin, or various natural antigens were used to induce the cells. The 28-amino acid form of somatostatin had some effects on gamma IFN yields but the first 14-amino acid fragment of this peptide moiety did not. No effect of any of these compounds was observed on IFN bioactivity. These studies indicate SMS may have some regulatory action on the secretion of immunomodulators in vitro but the concentrations required are well above those encountered under physiologic circumstances, suggesting SMS may not play an important regulatory role governing such secretion in vivo.     

Effect of isorhapontigenin on respiratory burst of rat neutrophils

The effect of Isorhapontigenin (Iso) isolated from Belamcanda chinensis on respiratory burst of rat neutrophils was investigated. Iso (1, 10, 100 mmol/l) showed an inhibitory effect on superoxide anion and hydrogen peroxide production in phorbol myristate acetate (PMA) activated rat neutrophils in a concentration-dependent manner. Scanning electron microscopy detected that Iso (100 mmol/l) protected against surface changes in rat neutrophils stimulated with PMA. Also, 100 mmol/l Iso inhibited the release of beta-glucuronidase from the activated neutrophils. Electron-spin resonance (ESR) detected that Iso scavenged oxygen free radicals generated in the PMA activated Neutrophils. These results suggest that Iso inhibits respiratory burst of PMA-activated rat neutrophils by scavenging oxygen free radicals.     

Asparagine-linked glycosylation of cytochrome b558 large subunit varies in different human phagocytic cells

Cytochrome b558, an essential component of the respiratory burst of phagocytic cells, is the terminal electron donor to molecular oxygen that results in the formation of superoxide anion (O2-.). It is an integral membrane heterodimer that in neutrophils consists of a 22-kDa small subunit and a highly glycosylated 91-kDa large subunit. Identical core proteins often differ in glycosylation in different cell types and with some membrane glycoproteins, the glycosylation state may markedly affect function. In the present study, antisera reactive with cytochrome b558 large subunit was used for immunoblot analysis of the glycosylation pattern of this subunit from different types of phagocytic cells. Striking variability in the apparent m.w. of this broadly banding subunit was detected in five different phagocytic cell types (neutrophils 78,000 to 93,000; eosinophils 74,000 to 115,000; monocytes 82,000 to 99,000; dibutyryl cyclic AMP-induced HL-60 cells 79,000 to 103,000; dimethyl sulfoxide-induced HL-60 cells 77,000 to 110,000). However, after complete cleavage of N-linked oligosaccharides with endoglycosidase F, the core peptide of cytochrome b558 large subunit from these different cell types had the same Mr (58,000). Inhibition of N-glycosylation with tunicamycin in differentiating HL-60 cells resulted in the synthesis of immunoreactive protein of the same m.w. and banding pattern as seen after endoglycosidase F cleavage. These tunicamycin treated cells retained some capacity to generate superoxide anion when stimulated with PMA. We conclude that the identity of the N-linked oligosaccharides of the cytochrome b558 large subunit differ in various phagocytic cells. All N-linked glycans on cytochrome b558 in all cell types examined were of the complex type as defined by resistance to endoglycosidase H cleavage. N-linked glycosylation of the cytochrome b558 large subunit may not be essential for activation of the respiratory burst.     

Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein and conversion of low-density lipoprotein to a cytotoxin

Human monocytes, upon activation with opsonized zymosan, altered low-density lipoprotein (LDL) during a 24-h co-incubation, resulting in its oxidation and acquisition of cytotoxic activity against target fibroblast cell lines. Both the oxidation of LDL and its conversion to a cytotoxin were enhanced with time of incubation, with the most substantial changes occurring after 6 h of culture of LDL with activated monocytes. Unactivated monocytes did not mediate either alteration. Superoxide anion (O2-) participated in both the oxidation of LDL and its conversion to a cytotoxin since addition of superoxide dismutase (SOD) at the beginning of the co-incubation inhibited, in a concentration dependent fashion, both the monocyte-mediated oxidation and the monocyte-mediated conversion of LDL to a cytotoxin. As expected, the rate of superoxide anion release was greatest during the respiratory burst, very early in the 24-h incubation (0 to 2 h); however, exposure of LDL to monocytes during the respiratory burst was not required for LDL oxidation. The lower levels of O2- released by the cells hours after the respiratory burst had subsided were sufficient to lead to the initiation of LDL oxidation. Three results indicated that the oxidative modification of LDL into a cytotoxin required O2(-)-independent free radical propagation after O2(-)-dependent initiation. First, oxidation of LDL exposed to the activated, superoxide anion-releasing monocytes for 6 h could be almost completely blocked by the addition at 6 h of the general free radical scavenger butylated hydroxytoluene, but not by SOD. Second, LDL oxidation proceeded even after removal of LDL from the superoxide anion-producing, activated cells after various durations of exposure. Third, the development of substantial levels of lipid peroxidation products and the development of greater cytotoxicity occurred after 6 h of exposure of LDL to activated cells, long after peak O2- release had subsided. These results lead us to conclude that monocyte-mediated oxidation of LDL, leading to its transformation into a cytotoxin, requires release of O2- occurring as a result of activation but not necessarily during the respiratory burst, and also requires O2(-)-independent free radical propagation. The modification of LDL into a potent toxin by activated monocytes may explain the tissue damage in atherosclerotic lesions and other pathologic sites in which inflammatory cells congregate.     

The effect of somatostatin on baseline and stimulated acid secretion and vascular histamine release from the totally isolated vascularly perfused rat stomach

The effect of somatostatin-(1-14) (S1-14) on the gastrin- and histamine-induced acid secretion and gastrin-evoked vascular histamine release was studied in isolated vascularly perfused rat stomachs being continuously perfused by a gassed buffer containing 10% ovine erythrocytes and 50 microM isobutyl methylxanthine (IMX). Concentrations of gastrin (520 pM) and histamine, (0.5 microM) were chosen to give acid secretion in the same range (61.5 +/- 7.0 and 49.4 +/- 9.4 mumol/60 min). S1-14 induced a concentration-dependent decrease in acid secretion stimulated by both gastrin and histamine. Even at the lowest concentration examined (0.1 nM) somatostatin gave a significant inhibition of both gastrin- and histamine-stimulated acid secretion. The inhibitory effect was, however, most marked for gastrin-stimulated acid secretion (P less than 0.05 at 1 nM concentration of S1-14). Gastrin gave an immediate and marked vascular histamine release which was inhibited by somatostatin in the higher concentrations (1.0 and 5.0 nM). Somatostatin at the lowest concentration tested (0.1 nM) did not inhibit the gastrin-induced vascular histamine release although it did inhibit acid secretion. Furthermore, baseline histamine release was not affected by somatostatin. This study suggests that somatostatin inhibits acid secretion both via a direct effect of the parietal cell and by inhibiting gastrin-induced histamine release. Baseline histamine release is regulated by a mechanism not sensitive to somatostatin.     

Activation by gamma interferon of human macrophage capability to produce toxic oxygen molecules is accompanied by decreased Km of the superoxide-generating NADPH oxidase

Capability to release superoxide anion in response to phorbol myristate acetate by intact cells has been compared with Kinetic properties of NADPH oxidase by lysates of human monocytes and monocyte-derived macrophages. Maturation of monocytes in vitro is accompanied by substantial decrease of the capability to release superoxide anion in response to phorbol myristate acetate. Exposure of mature macrophages to recombinant interferon gamma enhances respiratory burst activity up to 3-4 fold. Modifications of NADPH oxidase accompany changes in the ability to release superoxide anion. The affinity of the oxidase for its substrate is higher in monocytes and gamma interferon treated macrophages, while Vmax is not changed.     

Vasoactive intestinal peptide inhibits the respiratory burst in human monocytes by a cyclic AMP-mediated mechanism

The neuropeptide vasoactive intestinal peptide (VIP) was shown to inhibit the production of reactive oxygen compounds (respiratory burst) in monocytes activated by serum opsonized zymosan. Reactive oxygen compounds are of importance for host defence against micro-organisms and cancer, but normal tissues are also susceptible to damage from these reactive substances. Maximum inhibition of respiratory burst was 40% by 0.1 microM VIP (ID100), while ID50 for the VIP effect was 0.36 nM VIP. PHM-27, closely related to VIP on the basis of the amino acid sequence, inhibited the respiratory burst with much lower potency (ID50 = 60 nM, ID100 = 1 microM). Secretin, related to VIP and PHM-27, produced no effect on the respiratory burst in monocytes. VIP was also shown to stimulate the cyclic AMP production in monocytes in a dose dependent manner. IBMX and forskolin, as well as the cyclic AMP analogue butyryl cyclic AMP were shown to produce an inhibition of the respiratory burst. In conclusion, this study showed that VIP inhibited the respiratory burst in monocytes by a cyclic AMP-mediated mechanism, and serves to establish still another role for VIP as a mediator in the neuro-immune axis.     

Somatostatin down-regulates the expression and release of endozepines from cultured rat astrocytes via distinct receptor subtypes

Endozepines, a family of regulatory peptides related to diazepam-binding inhibitor (DBI), are synthesized and released by astroglial cells. Because rat astrocytes express various subtypes of somatostatin receptors (sst), we have investigated the effect of somatostatin on DBI mRNA level and endozepine secretion in rat astrocytes in secondary culture. Somatostatin reduced in a concentration-dependent manner the level of DBI mRNA in cultured astrocytes. This inhibitory effect was mimicked by the selective sst4 receptor agonist L803-087 but not by the selective sst1, sst2 and sst3 receptor agonists L779-591, L779-976 and L797-778, respectively. Somatostatin was unable to further reduce DBI mRNA level in the presence of the MEK inhibitor U0126. Somatostatin and the sst1, sst2 and sst4 receptor agonists induced a concentration-dependent inhibition of endozepine release. Somatostatin and the sst1, sst2 and sst4 receptor agonists also inhibited cAMP formation dose-dependently. In addition, somatostatin reduced forskolin-induced endozepine release. H89 mimicked the inhibitory effect of somatostatin on endozepine secretion. In contrast the PLC inhibitor U73122, the PKC activator PMA and the PKC inhibitor calphostin C had no effect on somatostatin-induced inhibition of endozepine release. The present data demonstrate that somatostatin reduces DBI mRNA level mainly through activation of sst4 receptors negatively coupled to the MAPK pathway, and inhibits endozepine release through activation of sst1, sst2 and sst4 receptors negatively coupled to the adenylyl cyclase/PKA pathway.     

Polymorphonuclear leukocyte-mediated, antibody-dependent, cellular cytotoxicity against tumor cells: dependence on oxygen and the respiratory burst.

Experiments were done to determine 1) whether the respiratory burst of superoxide anion (O2-) production in polymorphonuclear leukocytes (PMN) is triggered during antibody-dependent killing of tumor cells and 2) whether O2- production is essential for cytotoxicity. Three parameters of the respiratory burst (1-14C-glucose oxidation, oxygen consumption, and O2- release) were increased 2.5- to 7.3-fold during killing of antibody-primed tumor cells by human PMN. Added catalase and superoxide dismutase did not inhibit lysis, possibly because these enzymes were unable to diffuse into the inter-plasma-membrane space between killer and target cells. Evidence for an O2- requirement for cytotoxicity was the fact that concentrations of amobarbital or phenylbutazone sufficient to inhibit the cyanide-insensitive respiration of PMN also inhibited cytotoxicity. Also, hypoxic conditions inhibited cytotoxicity from 29 to 73%. The requirement for oxygen was most likely related to O2- generation and not mitochondrial respiration since cyanide and azide, which inhibit mitochondrial respiration, increased cytotoxicity.     

Binding of somatostatin to guinea-pig pancreatic membranes: regulation by ions

Somatostatin receptors were characterized on guinea-pig pancreatic acini membranes using 125I-[Tyr11] somatostatin 14 as a radioligand. In 0.1 mM Ca2+ buffer the binding was saturable and slowly reversible, exhibiting a single class of high affinity binding sites (KD = 0.15 +/- 0.03 nM) with a maximal binding capacity (B max) of 178 +/- 18 fmol/mg protein. In 30 nM) free Ca2+ buffer, the binding was highly reversible. Affinity and B max were decreased by about 2-fold. Ca2+ exhibited an EC50 of 2.4 +/- 0.9 microM to potentiate the binding of somatostatin. Na+, but not K+, inhibited the binding: Bmax was decreased with no change in affinity. Somatostatin analogs inhibited the binding of 125I-[Tyr11] somatostatin 14. The relative potencies were: somatostatin 14 greater than somatostatin 28 = [Nle8]somatostatin 28 greater than [D Tryp8, D Cys14]somatostatin 14.     

Somatostatin induces rapid contraction of neuroendocrine cells

The peptide hormone somatostatin, as well as the somatostatin analog octreotide, induces rapid morphological changes in neuroendocrine cells. The effect can be detected in less than 2 min: retraction fibers are formed, cells round up and cell-cell contacts are broken. Somatostatin-dependent cell contraction is inhibited by Y-27632, indicating that this effect is dependent on Rho kinase. In BON1 cells, the somatostatin-induced inhibition of forskolin-induced secretion of chromogranin A is not blocked by Y-27632. It is therefore concluded that the inhibitory effect of somatostatin in forskolin-stimulated cells is not dependent on cell contraction.     

Somatostatin structure-activity studies in the stomach

Somatostatin may inhibit gastric exocrine functions independent of blockade of gastrin secretion. In order to further investigate this suppressive effect, somatostatin derivatives were injected to cats bearing a cannulated gastric fistula under pentagastrin stimulation. Results showed that somatostatin-14 was more potent than somatostatin-28 in this particular model. Analogues with substituted residues exhibited a variable spectrum of actions on hormone release and gastric function. A cyclic pentapeptide was deprived of gastric or GH inhibitory properties whereas the related peptide with a benzyl-protecting group on Thr was only devoid of gastric effect. The octapeptide SMS 201-995 was described as a potent inhibitor of gastric secretion in comparison with natural somatostatin in rats and also in humans, but was unable to induce maximal suppression of acid output in the cat model. Differences in gastric effect of different derivatives could be explained on the basis of binding to a selective subset of receptors, since at least two binding sites have been identified in the stomach mucosa. Serial studies with short cyclic somatostatin should help to establish a clear relationship between peptide structure and inhibition of gastric secretion.     

Stimulation of the respiratory burst in peripheral blood monocytes by lipoteichoic acid. The involvement of calcium ions and phospholipase A2

Lipoteichoic acid (LTA) from Streptococcus faecalis stimulates the respiratory burst in peripheral blood monocytes (mon), as measured by cytochrome C reduction. The effect of LTA was time and dose dependent. LTA stimulated the respiratory burst in a biphasic manner within a range of 1 to 1000 ng/ml.10(6) mon, with maximal activity at 50 ng/ml. At this concentration LTA increased the activity from 0.97 +/- 0.2 to 4.88 +/- 0.2 nmol.10(6) mon/20 min. The role of calcium ions in the effect of LTA in stimulating respiratory burst was studied by changing the availability of calcium ions in the medium, and by measuring the effect of LTA on 45Ca2+ uptake and on intracellular Ca2+ levels. Removal of extracellular calcium ions in the presence of the calcium chelator EGTA, abolished the LTA-stimulated respiratory burst. LTA (50 ng/ml) was found to increase 45Ca2+ uptake into monocytes within seconds (from 2200 +/- 242 in the untreated cells to 4642 +/- 365 cpm/min in the LTA-treated mon). At this concentration, LTA stimulated an immediate rise in the intracellular free Ca2+ concentration to 155 +/- 15 nM as compared with 120 +/- 14 nM in the unstimulated monocytes. LTA caused a specific release of arachidonic acid indicating the involvement of phospholipase A2 in the transduction signal stimulating the respiratory burst by LTA.     

111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation.

Somatostatin receptor-positive human tumors can be detected using radioiodinated analogues of somatostatin, both in vitro and in vivo. [123I-Tyr3]-octreotide has been successfully used in the visualization of somatostatin receptor-positive tumors by gamma camera scintigraphy, but this radiopharmaceutical has some major drawbacks, which can be overcome with other radionuclides such as 111In. As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201-995) was prepared. This peptide, [DTPA-D-Phe1]-octreotide (SDZ 215-811) binds more than 95% of added 111In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, [DTPA-D-Phe1]-octreotide and non-radioactive [115In-DTPA-D-Phe1]-octreotide. The binding of [111In-DTPA-D-Phe1]-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatostatin as well as by octreotide, suggesting specific binding of [111In-DTPA-D-Phe1]-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated [Tyr3]-octreotide, but indium-labeled [DTPA-D-Phe1]-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that [111In-DTPA-D-Phe1]-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.     

The immune response of white shrimp Litopenaeus vannamei and its susceptibility to Vibrio alginolyticus under nitrite stress

The white shrimp Litopenaeus vannamei were challenged with tryptic soy broth (TSB)-grown Vibrio alginolyticus at a dose of 1 x 10(6) colony-forming units (cfu) shrimp(-1), and then placed in water containing concentrations of nitrite-N at 0 (control), 1.12, 5.15, 11.06 and 21.40 mg l(-1). Mortality of shrimp in 5.15, 11.06 and 21.40 mg l(-1) was significantly higher than those in the control solution after 48-168 h. L. vannamei that had been exposed to control, 0.98, 4.94, 9.87 and 19.99 mg l(-1) nitrite-N for 96 h were examined for THC (total haemocyte count), phenoloxidase activity, and respiratory burst (release of superoxide anion). The THC and phenoloxidase activity decreased when the shrimp were exposed to 4.94, 9.87 and 19.99 mg l(-1) nitrite-N, whereas, the respiratory burst increased significantly at 9.87 and 19.99 mg l(-1) nitrite-N after 96 h. It is therefore suggested that nitrite in water caused a depression in the immune ability of L. vannamei and an increased susceptibility to V. alginolyticus infection, together with an increase of superoxide anion production, possibly to cytotoxic levels for the host.     

Pulses of somatostatin release are slightly delayed compared with insulin and antisynchronous to glucagon

It was early proposed that somatostatin-producing delta-cells in pancreatic islets have local inhibitory effects on the release of insulin and glucagon. Recent observations that pulses of insulin and glucagon are antisynchronous make it important to examine the temporal characteristics of glucose-induced somatostatin release. Analysis of 30 s fractions from the perfused rat pancreas indicated that increase of glucose from 3 to 20 mmol/l results in initial suppression of somatostatin release followed by regular 4-5 min pulses. During continued exposure to 20 mmol/l glucose, the pulses of somatostatin overlapped those of insulin with a delay of 30 s. Somatostatin and glucagon pulses were coupled in antisynchronous fashion (phase shift 2.4+/-0.2 min), supporting the idea that the delta-cells have a local inhibitory effect on glucagon release. It was possible to remove the pulses of somatostatin and glucagon with maintenance of the insulin rhythmicity by addition of 1 micromol/l of the P2Y(1) receptor antagonist MRS 2179.     

Effect of copper sulfate on the immune response and susceptibility to Vibrio alginolyticus in the white shrimp Litopenaeus vannamei

White shrimp Litopenaeus vannamei (Boone) held in 35 per thousand seawater were challenged with Vibrio alginolyticus at a dose of 3 x 10(5) colony-forming units (cfu) shrimp(-1), and then placed in water containing concentrations of Cu2+ at 0 (control), 1, 5, 10 and 20 mg l(-1). Mortality of shrimp in 5, 10 and 20 mg l(-1) Cu2+ was significantly higher than those in 1 mg l(-1) Cu2+ and the control solution after 24-96 h. In another experiment, L. vannamei which had been exposed to control, 1, 5, 10 and 20 mg l(-1) Cu2+ for 24, 48 and 96 h were examined for THC (total haemocyte count), phenoloxidase activity, respiratory burst (release of superoxide anion), phagocytic activity and clearance efficiency to V. alginolyticus. Copper concentrations at 1 mg l(-1) or greater for 24h resulted in decreased THC, phenoloxidase activity, phagocytic activity and clearance efficiency, whereas copper concentration at 20 mg l(-1) caused significant increase in respiratory burst of L. vannamei. In conclusion, concentration of Cu2+ at 1 mg l(-1) or greater increased the susceptibility of L. vannamei to V. alginolyticus infection by a depression in immune ability. The release of superoxide anion by L. vannamei exposed to 20 mg l(-1) Cu2+ was considered to be cytotoxic to the host.     

Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis.

Somatostatin and its analogs are active in the inhibition of SST receptor-positive endocrine neoplasms, but their activity and mechanism in nonendocrine tumors is not clear. Somatostatin potently inhibited growth of a Kaposi's sarcoma xenograft in nude mice, yet in vitro the tumor cells did not express any known somatostatin receptors and were not growth inhibited by somatostatin. Histological examination revealed limited vascularization in the somatostatin-treated tumors as compared with the controls. Somatostatin was a potent inhibitor of angiogenesis in an in vivo assay. In vitro, somatostatin inhibited endothelial cell growth and invasion. Migration of monocytes, important mediators of the angiogenic cascade, was also inhibited by somatostatin. Both cells types expressed somatostatin receptor mRNAs. These data demonstrate that somatostatin is a potent antitumor angiogenesis compound directly affecting both endothelial and monocytic cells. The debated function of somatostatin in tumor treatment and the design of therapeutic protocols should be reexamined considering these data.