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Patients with neuroendocrine tumors (NETs), malignancies of rare but still rising incidence, may be a group at higher risk of vitamin D insufficiency. The gastrointestinal tumor prevalence and somatostatin analog (SSA) therapy may cause vitamin D malabsorption. The aim of this study was to evaluate the serum level of vitamin D in NET patients. A total of 36 NET patients were enrolled into the experimental group and 16 individuals were enrolled into the control group. All patients were further classified into subgroups according to primary tumor localization (gastropancreatic, lung, and other NETs) or therapy (with or without SSA treatment). The concentrations of total 25(OH)D were assayed with Electrochemiluminescence immunoassay (ECLIA). Serum concentration of 25(OH)D in NET patients did not differ significantly from that of the control group. However, the average level of 25(OH)D in both groups met the criteria of vitamin D deficiency. Importantly, SSA therapy did not aggravate vitamin D deficiency. Moreover, the concentration of 25(OH)D in the studied group was not significantly influenced by primary tumor localization, patient age, or season. Vitamin D deficiency is a widespread disorder affecting both NET patients and individuals without other health problems, and SSA and gastrointestinal tumor localization do not exacerbate this condition.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms characterized by rising incidence. Moreover, the neuroendocrine cells were shown to express vascular endothelial growth factor (VEGF) and VEGF receptors. Therefore, angiomodulators could be potentially a new group of drugs enhancing still unsatisfactory effectiveness of NET therapy. The aim of this study was to assess the direct influence of angiomodulators: VEGF and five endogenous and exogenous antiangiogenic compounds (endostatin, interferon alpha [IFNα], rapamycin, JV1-36, semaxinib [SU5416]) on the growth of two NET cell lines: lung carcinoid H727 cell line and medullary thyroid cancer TT cell line in vitro . IFNα and rapamycin induced the inhibitory effect on H727 and TT cell viability and proliferation, increasing apoptosis and arresting the cell cycle. Also semaxinib (10 −5 M) inhibited proliferation of both cell lines. VEGF and endostatin did not influence the growth of H727 and TT cells. The inhibitory effect of IFNα, rapamycin and semaxinib on carcinoid and medullary thyroid cancer growth was revealed in our in vitro study, although some other antiangiogenic agents did not directly influence H727 and TT cell growth. Thus, IFNα and mTOR inhibitors as multidirectionally acting drugs with antiangiogenic effect could be potentially efficient in treatment of neuroendocrine tumors and are worth further studies.

Recent studies demonstrate that ghrelin can be an endogenous regulator of angiogenesis. We studied direct effects of human acylated (hAG) and unacylated (hUAG) ghrelin, as well as of rat acylated ghrelin (rAG) on the growth of HECa10 murine endothelial cells. Ghrelin was applied separately or together with D-Lys(3)-GHRP-6, which is commonly used as an antagonist of ghrelin receptor type 1a - GHS-R1a. The growth of HECa10 cells was assessed with Mosmann and in selected study conditions also with BrdU and TUNEL methods. Both hAG and hUAG (10(-5) M to 10(-12) M) inhibited the growth of HECa10 cells in 24h and 72 h cultures. Similarly, rAG decreased the growth of the cells after 24h (10(-7) M and 10(-11) M), and after 72 h (10(-7) M, 10(-8) M and 10(-11) M). Unexpectedly, D-Lys(3)-GHRP-6 itself also inhibited the growth of these cells at 10(-4) to 10(-6) M in 24h, 48 h (dose-response effect) and 72 h cultures. D-Lys(3)-GHRP-6 did not modify the inhibitory effect of rAG. However, D-Lys(3)-GHRP-6 at the concentration of 10(-4) M diminished, abolished or even reversed the inhibitory effect of hUAG in 72 h culture and this was dependent on ghrelin concentrations. These data indicate that both AG and UAG have antiangiogenic properties at least at the level of endothelial growth, through decreased metabolic activity of the cells or stimulation of apoptosis. D-Lys(3)-GHRP-6 (inhibitor of GHS-R1a) seems not to be an appropriate antagonist in this experimental condition. Similar effects of these substances on HECa10 cells suggest that they are not mediated by GHS-R1a.

Background: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. Methods: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. Results: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. Conclusions: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases.

Some of the antagonists of growth hormone-releasing hormone (GHRH) are able to inhibit the growth of various experimental human cancers. The antitumor effects of first antagonists seemed to be dependent mainly on the disruption of pituitary secretion of growth hormone (GH), followed by the reduction in the levels of circulating insulin-like growth factor (IGF)-1, an important growth factor for cancer cells. It seems obvious, that growth hormone deficiency (GHD) induced by GHRH antagonists with all its complications, could limit the beneficial effects of GHRH antagonists therapy, and decrease patients' quality of life. The discovery of local autocrine/paracrine production of GHRH and other related growth factors in many tumoral tissues, in combination with the wide expression of GHRH receptors on cancer cells, directed the research to the synthesis of more potent GHRH antagonists. These compounds exert strong inhibitory effects directly on tumor growth, with scarce endocrine action. The receptor-mediated mechanisms comprise complex and still not completely understood effects on intracellular signaling pathways that are strictly related to human tumorigenesis. This review summarizes recent patents and latest observations on the antineoplastic role of GHRH antagonists in human tumors with emphasis on potential therapeutic applications in clinical oncology.

Somatostatin (SS) was originally discovered as a hypothalamic neurohormone which inhibits growth hormone secretion. The synthesis of the first two metabolically stabilized and more potent SS analogs, octreotide and lanreotide leads to the establishment of applications for them and to introduction into routine therapies. The effectiveness of octreotide or lanreotide in controlling symptoms and GH/IGF-I hypersecretion in acromegalic patients, both preoperatively and postoperatively is well proven. Similarly, these drugs are also very effective in the treatment of TSH-secreting adenomas. The introduction of these drugs into therapy of the functional neuroendocrine tumors of the gastrointestinal tract was a crucial step in the treatment. Octreotide and lanreotide are the drugs of choice in the treatment of patients with: VIPoma, glucagonoma and carcinoid syndrome. Somatostatin receptor scintigraphy with OctreoScan has been recommended as the best imaging technique in these tumors in the localization and staging procedure. SS analogs, coupled to radioisotope or cytotoxic drugs, create another class of SS molecules, very promising in the therapy of the endocrine glands tumors and in other tumors. Another class of SS analogs comprises hybrid molecules, which are chimera of sst2 agonist and D2 agonist, possessing more potent activity than these agonists, applied together.

Somatostatin (SST) was firstly discovered as a hypothalamic hormone inhibiting GH secretion. Despite its broad inhibitory effects on both endocrine and exocrine secretions, natural SST has limited therapeutic potential owing to its short plasma half-life. The synthesis of the first two metabolically stabilized and more potent SST analogs (octreotide and lanreotide) established the use of SST peptide therapy. The discovery of the five SST receptor (sst(1-5)) subtypes in the 1990s further enhanced our understanding of the biological roles of SST, created new therapeutic opportunities and highlighted the limitation of 'classical' SST analogs, which act mainly via receptor subtype 2 and are unable to reproduce all actions of native SST. To diminish these limitations, new SST analogs highly selective for particular receptor subtypes, together with so-called 'universal' analogs acting on multiple receptor subtypes, have been developed. These compounds have shown promise in preclinical studies and might further advance the use of SST analog therapy in the future. The development of SST analogs coupled to radioisotopes or cytotoxic drugs, which allows the selective destruction of tumor cells overexpressing sst receptors, constitutes another field of progress.

Oestrogens are known to enhance angiotensin biosynthesis by increasing the elaboration of its precursor, angiotensinogen. On the other hand, we found that inhibition of angiotensin-converting enzyme (ACE) suppressed the proliferative response of the rat anterior pituitary gland to oestrogens. To answer the question whether the angiotensin system is involved in the control of the cell proliferation of the uterine epithelium, the effects of an ACE inhibitor, enalapril maleate, and of angiotensins II and IV, alone or together with losartan, an antagonist of angiotensin receptor type 1 (AT1), on endometrial epithelial cell proliferation have been studied. The experiments were performed on ovariectomized female Wistar rats. In the first experiment the animals were injected with a single dose of oestradiol benzoate or received an injection of solvent only. Half of the oestrogen-treated rats were injected additionally with enalapril maleate (EN, twice daily). The incorporation of bromodeoxyuridine (BrDU) into endometrial cell nuclei was used as an index of cell proliferation. It was found that oestradiol alone dramatically increased the BrDU labelling index (LI) of endometrial cell nuclei, and this effect was partially blocked by the simultaneous treatment with EN. In the second experiment, the animals were injected intraperitoneally with angiotensin II (AII), angiotensin IV (AIV) or saline, alone or together with losartan. It was found that AIV induced an increase in the LI in uterine epithelium, and this effect was not blocked by the simultaneous treatment with losartan. The increase in LI in uterine epithelium was also observed in the rats treated with AII and with losartan. These findings suggest an involvement of angiotensin IV in the control of uterine epithelium cell proliferation.

Wstep: Guzy chromochlonne (pheochromocytoma/paraganglioma) nalezą do lagodnych lub zlośliwych nowotworow neuroendokrynnych. Wobec niezadowalającej skuteczności standardowych sposobow leczenia pacjentow z rozsianą postacią choroby, wciąz poszukuje sie nowych metod terapii, w tym mozliwości skutecznego leczenia celowanego. W związku ze wzmozonym unaczynieniem tych nowotworow, preparaty o dzialaniu antyangiogennym mogą potencjalnie stanowic nową grupe lekow stosowanych w leczeniu pheochromocytoma/paraganglioma. Material i metody: W badaniu oceniano wplyw roznych angiomodulatorow: VEGF (naczyniowo-środblonkowy czynnik wzrostu) oraz pieciu endo- i egzogennych czynnikow antyangiogennych (endostatyna; IFN-alfa [interferon alfa]; rapamycyna — inhibitor szlaku mTOR [mammalian target of rapamycin]; JV1-36 and SU5416 [semaxinib]) na wzrost szczurzej linii pheochromocytoma PC12. Wyniki: IFN-alfa (105 U/mL) silnie hamowal wzrost komorek PC12 w hodowli 72 h, nasilając apoptoze i hamując cykl komorkowy. Rapamycyna w szerokim zakresie stezen (10-5 to 10-8 M) nieznacznie zmniejszala zywotnośc komorek PC12, a w stezeniu 10-5 M takze hamowala ich proliferacje. VEGF, endostatyna oraz JV1-36 nie wplywaly na wzrost lini PC12. Wnioski: W badaniu po raz pierwszy wykazano, ze IFN-alfa hamuje wzrost linii komorkowej pheochromocytoma PC12, a takze potwierdzono hamujący wplyw rapamycyny wobec tej linii komorkowej. Uzyskane wyniki sugerują zatem, ze IFN-alfa oraz inhibitory szlaku mTOR mogą byc potencjalnie skuteczne w leczeniu zlośliwych postaci guzow chromochlonnych i zachecają do dalszych badan w tym kierunku. (Endokrynol Pol 2013; 64 (5): 368–374)

The protective role of estrogens in the colon carcinogenesis has been suggested for many years and attributed mainly to estrogen receptor beta (ERbeta). However, the direct effect of estrogens and their action through ERbeta on the growth of colon cancer have been rarely studied. The aim of this study was to examine the effect of various concentrations (10(-4)-10(-12)M) of diarylpropionitrile (DPN)--a selective agonist of ERbeta--on the growth of murine MC38 colon cancer line. Moreover, the aim of this paper was the immunohistochemical assessment of estrogen and progesterone receptor expression in human colon tissues and in MC38 cells (only ERbeta). We found that DPN induced a growth inhibition of MC38 cancer (50-94% of control group) at the highest (10(-4)M) and two lowest concentrations (10(-11) and 10(-12)M). Furthermore, we detected a nuclear-cytoplasmic expression of ERbeta in human normal and neoplastic colon tissues and in the studied MC38 cancer cells. The inhibitory effect of DPN on the growth of MC38 colon cancer line suggests a possibility of using a selective estrogen receptor agonist in the treatment of colon cancer.

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.

At the present time only two long-acting somatostatin (SS) analogs, octreotide and lanreotide, are commonly used in the routine therapy. Both analogs have a high affinity mainly to a somatostatin receptor subtype 2 (SSTR2). The established indications for SS analogs treatment include acromegaly, neuroendocrine tumors of the pancreas and gastrointestinal tract, and some gastro-enterologic diseases (pancreatitis, gastrointestinal bleedings, refractory diarrheas, pancreatic and intestinal fistulas). The recent investigations allow to predict the enlargement of therapeutic applications of SS analogs. It concerns pituitary tumors other than somatotropinoma, tumors of other endocrine glands like thyroid and adrenal gland, as well as some non-endocrine tumors. The progress depends on the introduction of new SS analogs with high affinity for SS receptor subtypes other than SSTR2, because some tumors present the high expression of SSTR1 (e.g. prostatic cancers) or SSTR5 (e.g. colonic cancers). Great hopes are connected with the coupling of SS analogs with the radioactive isotopes or non-radioactive cytotoxic agents to destruct the neoplastic cells highly expressing the specific subtypes of SS receptors. The pre- or postoperative in vivo imaging of SS receptors by means of the receptor scintigraphy, as well as the post-operative identification of SS receptor subtypes in the excised tumor tissues using immunohistochemistry, should play an important role in the prediction of the effects of SS analog treatment. Beside oncology, new therapeutic applications of SS analogs could be presumed among others in ophthalmology; it concerns the treatment of progressive Graves-Basedow ophtalmopathy, diabetic retinopathy, glaucoma and corneal diseases connected with corneal vascularization.

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. This type of tumor is a rich source of basic fibroblast growth factor (bFGF), which possesses strong mitogenic and angiogenic properties. Pentosan polysulfate sodium (PPS) has been shown to exert antitumor activity by antagonizing the binding of bFGF to cell surface receptors. We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats. Chronic treatment with PPS did not cause any changes in the pituitary weight and serum prolactin concentration in comparison with untreated animals. The density of microvessels identified by CD-31 was also not affected by the tested drug. On the other hand, pentosan has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. Moreover, the TUNEL method has revealed an increased number of apoptotic bodies within the anterior pituitary after treatment with PPS. Despite the antiproliferative and proapoptotic activity of pentosan, the drug failed to inhibit tumor growth. This fact might be due to the lack of antiangiogenic activity of PPS in this experimental design.

e14621 Background: mCRC is one of the leading causes of cancer-related morbidity and mortality. Although CEA is a marker commonly used in clinical practice, its role in diagnosis and monitoring eff...

OBJECTIVES: The aim of this study was to compare the effects of two somatostatin (SS) analogs: octreotide and lanreotide administered separately or together with 5-fluorouracil (5-FU) with the action of 5-FU alone, on proliferation, apoptosis, proliferation/apoptosis (P/A) ratio and tumor weight in the murine transplantable Colon 38 cancer. MATERIALS AND METHODS: Two separate experiments were performed on male mice of B6D2F1 strain. In both experiments the animals were implanted subcutaneously with suspension of Colon 38 cancer cells. A few days later, in the first experiment, octreotide was given once daily for six days at the dose of 10mgr;g/animal and in the second experiment a single dose of lanreotide (1 mg/animal) was administered. 5-FU was treated once (in the first experiment) or twice (in the second experiment) at the dose of 70 mg/kg b.w. depending on the duration of the experiment. In both experiments the incorporation of bromodeoxyuridine into the tumor cell nuclei was used as an index of cell proliferation (labeling index - LI). The labeling of nuclear DNA fragmentation according to TUNEL method was considered as an index of apoptosis (AI). RESULTS: It has been found that both SS analogs, given separately, significantly decreased LI of tumor cells, increased their AI and decreased P/A ratio of Colon 38 tumors, as compared to controls. 5-FU given alone (in both experiments) significantly enhanced AI, decreased P/A ratio, but did not significantly change LI, as compared to controls. The joint treatment with 5-FU and each of the two SS analogs did not produce any additive effects either on proliferation or apoptosis. The tumor weight was significantly decreased only by the joint treatment with 5-FU and octreotide, as compared to the control group.

Background The risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro. Methods The cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method. Results hUAG (10 −6 , 10 −7 and 10 −10 M) inhibited MC38 cancer cell growth and, at some concentrations (10 −8 , 10 −9 , 10 −10 M), enhanced the antineoplastic effect of GHS-RA (10 −4 M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10 −4 M and stimulatory at 10 −5 and 10 −6 M. Moreover, GHS-RA at the highest examined concentration (10 −4 M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose-response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA. Conclusion The obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms.