Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands

Role of adiponectin and leptin on body development in infants during the first year of life

<p>Abstract</p> <p>Background</p> <p>The control of growth and nutritional status in the foetus and neonate is a complex mechanism, in which also hormones produced by adipose tissue, such as adiponectin and leptin are involved. The aim of this study was to evaluate levels of adiponectin, leptin and insulin in appropriate (AGA) and small for gestational age (SGA) children during the 1^styear of life and to correlate these with auxological parameters.</p> <p>Methods</p> <p>In 33 AGA and 29 SGA infants, weight, length, head circumference, glucose, insulin, adiponectin and leptin levels were evaluated at the second day of life, and at one, six and twelve months, during which a portion of SGA could show catch-up growth (rapid growth in infants born small for their gestational age).</p> <p>Results</p> <p>Both total and isoform adiponectin levels were comparable between AGA and SGA infants at birth and until age one year. These levels significantly increased from birth to the first month of life and then decreased to lower values at 1 year of age in all subjects. Circulating leptin concentrations were higher in AGA (2.1 ± 4.1 ng/ml) than in SGA neonates (0.88 ± 1.03 ng/ml, p < 0.05) at birth, then similar at the 1^stand the 6^thmonth of age, but they increased in SGA from six months to one year, when they showed catch-up growth. Circulating insulin levels were not statistically different in AGA and SGA neonates at any study time point. Insulin levels in both AGA and SGA infants increased over the study period, and were significantly lower at birth compared to one, six and 12 months of age.</p> <p>Conclusions</p> <p>During the first year of life, in both AGA and SGA infants a progressive decrease in adiponectin levels was observed, while a difference in leptin values was correlated with the nutritional status.</p

Effects of uremia and inflammation on growth hormone resistance in patients with chronic kidney diseases

Resistance to the anabolic action of growth hormone may contribute to the loss of strength and muscle mass in adult patients with chronic kidney disease. We tested this hypothesis by infusing growth hormone in patients to levels necessary to saturate hormone receptors. This led to a significant decrease of plasma potassium and amino acid levels in control and hyperkalemic patients with chronic kidney disease. These effects were completely or partially blunted in patients with elevated C-reactive protein levels. In forearm perfusion studies, growth hormone caused a further decrease in the negative potassium and protein balance of hemodialysis patients without inflammation but no effect was seen in patients with inflammation. Only IL-6 levels and age were found to be independent correlates in these growth hormone-induced variations in plasma potassium and blood amino acids. This shows that although a resistance to pharmacologic doses of growth hormone is not a general feature of patients with chronic kidney disease, there is a subgroup characterized by blunted growth hormone action. Our results support the hypothesis that uremia with inflammation, but not uremia per se, inhibits downstream growth hormone signaling contributing to muscle atrophy

Somatostatin and prostate cancer: role of somatostatin receptors in the control of tumor growth

The evidence that prostate cancer (PCa) expresses specific receptors for hormones and neuropeptides, including somatostatin (SRIF) receptors (SSRs) has driven the research towards the identification of new potential diagnostic/therapeutic paths besides the conventional treatment options. Although the first attempts has led to inconclusive results due to the heterogeneity of this tumor and to the complex mechanisms involved in the progression of PCa tumor growth, the potential role of SRIF and its synthetic analogues (SSAs) in the treatment of PCa represents an “open challenge” in the light of the new knowledge about SSR pathophysiology. Indeed, SRIF and SSAs can control tumor cell proliferation by two separate mechanisms: a direct mechanism through the activation of the five specific SSRs or an indirect mechanism through the inhibition of secretion of several growth factors and hormones responsible for tumor cell proliferation. Since new SSAs specific for each receptor subtype, as well as bi-specific compounds and panligands have been synthetized, the identification of alternative SSR targets on PCa cells and the consequent employment of these new specific molecules in the treatment of advanced PCa (alone or in combination with traditional treatment options), could improve the prognosis particularly of those patients not responding to (anti-) hormonal therapy (hormone-refractory PCa patients)

Role of somatostatin analogues in the management of immunolymphoproliferative diseases

SS analogs may be of interest in the treatment of lymphoproliferative malignancies, although controlled studies are warranted to investigate the efficacy of the current available analogs. A promising approach in refractory patients with SSR positive malignant lymphomas may be radionuclide-targeted therapy. Furthermore, the development of receptor-based localization and antitumor strategies may be extended to other G protein-coupled receptors. This could be valid for two different important reasons: first, neuropeptide receptors homo- and heterodimerization has been recently shown occurring in transfected cell lines and involves different subtypes of SSR, as well as SSR and receptors for dopamine (50-61). Dimer formation seems to enhance or modify the transduction pathway activated by the monomeric receptor. From the other hand, in vivo imaging techniques of tumor via receptors for other well known neuroeptides, such as bombesin, vasoactive intestinal polypeptide, substance P, gastrin, have been already employed to visualize many neoplasms, and ligand-binding studies clearly demonstrated neuroreceptor binding sites in human tumors. Finally, cytotoxic analogs of ligands for these receptors have been developed and displayed an antiproliferative effect in experimental conditions. Whether these new agents can be of value for both diagnostic and therapeutic purposes in lymphoproliferative diseases is still unknown, however, their development represents an innovative and promising perspective

Somatostatin receptor pathophysiology in the neuroendocrine system

The actions of somatostatin (SRIF) are mediated by specific G protein-coupled receptors, named SRIF receptor (SSTR) subtypes 1, 2, 3 and 5. SRIF binding to SSTR activates a series of second messenger systems, resulting in the inhibition of calcium channels and adenylate cyclase activity, ultimately leading to inhibition of hormone secretion, while stimulation of other second messengers, such as phosphotyrosine phosphatases play a role in the control of cell growth. The SSTR and dopamine receptor families share a 30% sequence homology and appear to be structurally related. The knowledge on the pathophysiology of these two families of G protein-coupled receptors in neuroendocrine tumors has progressively increased due to the new insights in receptor dimerization, internalization and trafficking. Depending on the expression of different SSTRs in tissues, their combinations and interactions affect the functionality of the subtypes expressed and the influence of the microenvironment, the response to ligands and, by consequence, the response to treatment can be very different. \ua9 2013 Expert Reviews Ltd

Pancreatic Islet Cell Tumor Secreting Insulin-Like Growth Factor Type-II in a Dog

7-year-old, intact female, Gordon Setter was examined for a 6-month history of progressive weakness and ataxia without loss of appetite or change in weight. The owner reported a slight improvement in the signs after food consumption. The dog was kept indoors, regularly vaccinated, and fed a commercial maintenance diet. Physical examination revealed weakness, difficulty in holding quadrupedal posture, and mild muscle hypotrophy. No abnormalities were detected in the CBC, morphologic evaluation of the smear, and coagulation profile. Biochemical profile showed moderate hypoglycemia on fasting (57 mg/dL; range 80–120 mg/dL). Abdominal ultrasound showed an hypoechoic pancreatic lesion of 23 mm in diameter, with indistinct margins and poorly contrasting with adjoining structures. Eco-guided fine needle biopsy of the lesion was performed. The cytologic specimen contained a large number of naked nuclei on a cytoplasmic background with indistinct margins, occasionally acinar structures with moderate anisokaryosis. The cytologic pattern, together with clinical signs, suggested neuroendocrine tumor. Abnormalities were not detected on chest X-ray in 3 standard projections. Serum concentration of insulin was 0.5 mIU/mL (range 4–16 mIU/mL). Serum concentration of insulin-like growth factor type II (IGF-II) was evaluated by immunoradiometric assay (IRMA) after chromatographic separation. Five hundred microliters of serum were obtained from the dog and gel-filtered by fast protein liquid chromatography on HyPrep Sephacryl S-200 High Resolution column (GE Healthcare, Amersham Place, Little Chalfont, Buckinghamshire, UK) in a buffer containing 50 mM NaH2PO4, 0.15 M NaCl, 0.02% NaN3 ,p H 7.2. Samples were eluted at 0.8 mL/min and collected at 3minute intervals. 1 The 44 fractions collected were pooled and tested for IGF-II immunoreactivity as follows: fractions 8–11 corresponding to the 150 kDa ternary complex, fractions 12–16 corresponding to the 45 kDa binary complex, and fractions 24–27 corresponding to the free form of IGF-II. The fraction of IGF-II bound to insulin-like growth factor binding protein (IGFBP)-3 and acid labile subunit (ALS) forming a 150-kDa complex was 0.8 ng/mL. Similarly to normal dogs, IGF-II was only measurable in the 150 kDa region and undetectable in the others. IGF-II was measured by IRMA with reagents kit provided by DSL, a on acid ethanol pretreated samples. 2 The sensitivity of the assay was 0.13 ng/mL; the intra-assay and interassay coefficients of variation were 5.3 and 8.7%, respectively. No detectable cross-reactivity was found against IGF-I, up to 480,000 ng/mL, proinsulin, up to 2mg/mL, and insulin, up to 4.3mg/mL