Current Prospects for Adrenocortical Carcinoma Pharmacotherapy.

Adrenocortical carcinoma (ACC) is a rare but very aggressive malignancy of the endocrine system with specific biology characterized frequently by hormonal activity and high aggressiveness, resulting usually in locally-invasive or metastatic disease at the time of initial diagnosis. Despite an intense multidirectional search for novel strategies, there has been no satisfactory improvement in the effectiveness of standard therapy currently used in the clinic. ACC diagnosis usually means poor prognosis. Thus, the necessity to identify and implement novel and more effective treatment of ACC in clinical management remains constantly an ambitious challenge. The review briefly summarizes the current management of adrenocortical carcinoma and focuses mainly on novel prospects for ACC pharmacotherapy, including targeted therapies, immunotherapy and checkpoint inhibitors, theranostics, and at last, the individualized molecular approach based on the exact identification of specific genetic profile of ACC cells using next-generation sequencing methods as the next-generation perspective for precisely personalized therapy.

IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms.

Pentabromobenzylisothioureas are antitumor agents with diverse properties, including the inhibition of MAPK15, IGF1R and PKD1 kinases. Their dysregulation has been implicated in the pathogenesis of several cancers, including bronchopulmonary neuroendocrine neoplasms (BP-NEN). The present study assesses the antitumor potential of ZKKs, a series of pentabromobenzylisothioureas, on the growth of the lung carcinoid H727 cell line. It also evaluates the expression of MAPK15, IGF1R and PKD1 kinases in different BP-NENs. The viability of the H727 cell line was assessed by colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) and its proliferation by BrdU (5-bromo-2'-deoxyuridine) assay. Tissue kinase expression was measured using TaqMan-based RT-PCR and immunohistochemistry. ZKKs (10-4 to 10-5 M) strongly inhibited H727 cell viability and proliferation and their antineoplastic effects correlated with their concentrations (p < 0.001). IGF1R and MAPK15 were expressed at high levels in all subtypes of BP-NENs. In addition, the SCLC (small cell lung carcinoma) patients demonstrated higher mRNA levels of IGF1R (p = 0.010) and MAPK15 (p = 0.040) than the other BP-NEN groups. BP-NENs were characterized by low PKD1 expression, and lung neuroendocrine cancers demonstrated lower PKD1 mRNA levels than carcinoids (p = 0.003). ZKKs may suppress BP-NEN growth by inhibiting protein kinase activity. Our results suggest also a possible link between high IGF1R and MAPK15 expression and the aggressive phenotype of BP-NEN tumors.

Elevated serum concentrations of IGF-1 and IGF-1R in patients with thyroid cancers.

BACKGROUND: The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS: The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS: 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS: Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS: Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.

Dysregulation in IGF-1R, FGFR4 and ßKlotho signaling in patients with medullary thyroid cancer.

BACKGROUND: Medullary thyroid cancer (MTC) is a relatively rare thyroid neoplasm derived from neuroendocrine C cells which secrete calcitonin. αKlotho (αKL) and ßKlotho (ßKL) are transmembrane proteins which modulate different signaling systems, such as endocrine FGFs and IGF1 pathways. Dysregulation of the FGF19/FGFR4/ßKL and IGF-1/IGF-1R/αKL signaling axes has been implicated in the pathogenesis of several cancers. However, their role in the pathogenesis of MTC has not been determined. METHODS: The aim of this study was to assess αKL, ßKL, FGF19, IGF-1, FGFR4, and IGF-1R concentrations in a group of 11 patients with medullary thyroid cancer (MTC). The control group consisted of 20 healthy volunteers. Serum concentrations of these factors were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGFR4 and IGF-1R were found in patients with MTC as compared to controls. CONCLUSIONS: Our results indicate that a disrupted signaling pathway for ßKL, FGFR4 and IGF-1R may play a role in the development of medullary thyroid cancers. However, further studies are required to confirm these findings and to use this knowledge in clinical practice.

Estimation of vitamin D status in patients with secondary and primary hypothyroidism of different etiology.

BACKGROUND: Though vitamin D deficiency is a global problem with wide spectrum of severe public health consequences, inadequate vitamin D status still remains one of the most common and untreated medical conditions. Thyroid diseases, including hypothyroidism, also represent the most frequent endocrinopathies in general population. OBJECTIVES: To determine the vitamin D status in hypothyroid patients and to ascertain the status of thyroid hormone replacement. METHODS: The 25(OH)D concentrations (ECLIA) in 71 hypothyroid patients recruited in the Outpatient Clinic of Endocrinology or Department of Clinical Endocrinology were assessed. The examined group was composed of 59 subjects diagnosed with primary hypothyroidism of different etiology and 12 patients with secondary hypothyroidism. The control group included 16 healthy individuals. RESULTS: Mean serum 25(OH)D concentration in healthy volunteers was significantly lower than in hypothyroid subjects (13.09±1.63 vs. 19.92±1.37 ng/mL). Patients with a history of thyroidectomy presented with significantly higher mean 25(OH)D concentration than controls (23.25±2.75 vs. 13.09±1.63 ng/mL). Mean serum 25(OH)D concentration in effectively treated hypothyroidism was significantly higher than in controls (21.90±1.47 vs. 13.09±1.63 ng/mL) or undertreated hypothyroidism (21.90±1.47 vs. 13.52±3.39 ng/mL). Hypothyroid patients aged under 60 years presented with significantly lower mean 25(OH)D concentration than elders (16.46±1.54 vs. 24.39±1.18 ng/mL). The major 25(OH)D deficient (≤10 ng/mL) or deficient (≤20 ng/mL) hypothyroid patients were significantly younger than those with 25(OH)D concentrations exceeding 10 ng/mL or 20 ng/mL respectively. CONCLUSIONS: These findings confirm the necessity for vitamin D status improvement in the general population and more effective healthcare of hypothyroid patients.

Alteration in the serum concentrations of FGF19, FGFR4 and ßKlotho in patients with thyroid cancer.

INTRODUCTION: ßKlotho (ßKL) is known to act as co-receptor for fibroblast growth factor receptor 4 (FGFR4) which is the main cognate receptor for fibroblast growth factor 19 (FGF19). Dysregulation of this FGF19/FGFR4/ßKL signaling axis has been implicated in the pathogenesis of several cancers. However, its role in the pathogenesis of thyroid cancer has not been determined. MATERIALS AND METHODS: The aim of this study was to assess FGF19, FGFR4 and ßKL concentrations in a group of 36 patients with papillary thyroid cancer (PTC), 11 patients with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group consisted of 20 healthy volunteers. Serum FGF19, FGFR4 and ßKL concentrations were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGF19 were found in patients with PTC, FTC and ATC as compared with MNG group and controls. An elevation of FGFR4 serum concentration was observed in all thyroid cancer groups in comparison to MNG group and controls; however, in FTC group it was statistically insignificant. A positive correlation was found between ßKL and FGFR4 concentrations in PTC patients. The levels of ßKL, FGF19 and FGFR4 did not differ significantly between MNG group and healthy controls. CONCLUSIONS: Our results indicate that a disrupted FGF19/FGFR4/ßKL signaling pathway may play a role in the development of thyroid cancers. However, further studies are needed to elucidate the molecular mechanism of the neoplastic transition of thyroid epithelial cells.

Elevated Concentrations of SERPINE2/Protease Nexin-1 and Secretory Leukocyte Protease Inhibitor in the Serum of Patients with Papillary Thyroid Cancer.

Introduction. SERPINE2 and secretory leukocyte protease inhibitor (SLPI) are proteins with anticoagulant properties which could promote solid tumor growth. However, their role in the pathogenesis of thyroid cancer has not been determined. Materials and Methods. The aim of this study was to assess serum SERPINE2 and SLPI concentrations in a group of 36 patients with papillary thyroid cancer (PTC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum SERPINE2 and SLPI concentrations were measured using specific ELISA methods. Results. Significantly higher concentrations of SERPINE2 and SLPI were found in patients with PTC as compared with MNG and controls. Positive correlation was found between SERPINE2 and SLPI concentrations in PTC patients. The levels of SERPINE2 and SLPI did not differ significantly between MNG and healthy controls. Conclusions. Our results indicate that SERPINE2 and SLPI play a significant role in the development of papillary thyroid cancer and imply that the evaluation of serum concentrations of both anticoagulant molecules may be considered as additional marker for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors.

Somatostatin Analogs and Tumor Localization Do Not Influence Vitamin D Concentration in Patients with Neuroendocrine Tumors.

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.

Decreased serum level of IL-7 in patients with active Graves' disease.

BACKGROUND: Graves' disease (GD) is a common autoimmune disease which is one of the major causes of hyperthyroidism. Interleukin 7 (IL-7) has been recently reported to play an important role in various autoimmune diseases, but its role in the pathogenesis of GD has not been assessed. The aim of this study was to evaluate the levels of IL-7 and the soluble form of its receptor (sIL-7R) in the serum of GD patients, and to identify their association with disease activity. METHODS: A total of 37 GD patients were enrolled into the experimental group and 16 individuals into the control group. All patients were further classified into three subgroups: a GD-active group (hyperthyroidism and TRAb (thyroid stimulating hormone receptor antibody) >7.5 U/L) (N=15), a GD-inactive group (euthyreosis and TRAb<1 U/L) (N=8), and other GD patients (euthyreosis and TRAb>1 U/L) (N=14). Concentrations of IL-7 and sIL-7R were assayed with ELISA. Additionally, the relationship between IL-7 and sIL-7R serum concentrations with disease activity (free triiodothyronine [FT3], free thyroxine [FT4], thyroid stimulating hormone [TSH] and TRAb) was also analyzed. RESULTS: The serum concentrations of IL-7 in GD-active patients were significantly lower than those of the control group as well as the GD-inactive and GD-other groups. The serum level of IL-7 in GD patients negatively correlated with FT4 and TRAb concentrations. Moreover, no significant difference was observed in the serum level of sIL-7R in GD patients compared to the control group. CONCLUSIONS: These observations suggest that IL-7 may play a role in the pathogenesis of GD and may be associated with its clinical activity. To this end, the serum level of IL-7 could be an additional diagnostic biomarker predictive of the disease and could be particularly valuable for TRAb-negative GD patients.

Interferon alpha and rapamycin inhibit the growth of carcinoid and medullary thyroid cancer in vitro.

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.

Interferon alpha and rapamycin inhibit the growth of pheochromocytoma PC12 line in vitro.

INTRODUCTION: Pheochromocytomas are benign or malignant neuroendocrine tumours. The unsatisfactory efficacy of the traditional therapeutic methods for patients with metastatic disease results in a continuing search for more effective and targeted agents. Due to the increased vascularisation of these tumours, inhibitors of angiogenesis could be potentially a new group of drugs in pheochromocytoma/paraganglioma therapy. MATERIAL AND METHODS: The aim of this study was to evaluate the influence of angiomodulators: VEGF (vascular endothelial growth factor) and five endogenous and exogenous antiangiogenic compounds (endostatin; IFN-alpha [interferon alpha]; rapamycin - mTOR [mammalian target of rapamycin] inhibitor; JV1-36 and SU5416 (semaxinib]) on the growth of rat pheochromocytoma PC12 cell line. RESULTS: IFN-alpha (10(5) U/mL) strongly inhibited PC12 growth in a 72 h culture, increasing apoptosis and arresting the cell cycle. Rapamycin in a wide range of concentrations (10(-5) to 10(-8) M) induced a slight inhibitory effect on PC12 viability and decreased cell proliferation at the concentration of 10(-5) M. VEGF, endostatin and JV1-36 did not influence the growth of PC12. CONCLUSIONS: The study has shown for the first time that IFN-a inhibited the growth of pheochromocytoma PC12 line and confirmed the inhibitory action of rapamycin on these cells. The results suggest that IFN-alpha and mTOR inhibitors could be potentially effective in the therapy of malignant pheochromocytoma, and encourage further study in this field.

Modulation of ghrelin axis influences the growth of colonic and prostatic cancer cells in vitro.

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.

Angiotensins inhibit cell growth in GH3 lactosomatotroph pituitary tumor cell culture: a possible involvement of the p44/42 and p38 MAPK pathways.

The local renin-angiotensin system is present in the pituitary. We investigated the effects of angiotensins on GH3 lactosomatotroph cells proliferation in vitro and the involvement of p44/42 and p38 MAPK inhibitors in the growth-regulatory effects of angiotensins. Materials and Methods. Cell viability using the Mosmann method and proliferation by the measurement of BrdU incorporation during DNA synthesis were estimated. Results. Ang II and ang IV decreased the viability and proliferation of GH3 cells. Inhibitor of p44/42 MAPK attenuated the effects of ang II on cell viability and proliferation but did not affect the ang 5-8-dependent actions. Inhibitor of p38 MAPK prevented the decrease in the number of GH3 cells in ang-II- and ang-IV-treated groups. Conclusions. The growth-inhibitory effect of ang II is possibly mediated by the p44/42 MAPK. The p38 MAPK appears to mediate the inhibitory effects of both ang II and ang 5-8 upon cell survival.

The involvement of angiotensin type 1 and type 2 receptors in estrogen-induced cell proliferation and vascular endothelial growth factor expression in the rat anterior pituitary.

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.

The effects of angiotensin peptides and angiotensin receptor antagonists on the cell growth and angiogenic activity of GH3 lactosomatotroph cells in vitro.

The local renin-angiotensin system (RAS) is present in the pituitary gland, and inhibitory effects of angiotensins on the lactosomatotroph (GH3) cell growth have been revealed. The aim of this study was to examine the influence of various angiotensin peptides and angiotensin AT1, AT2, and AT4 receptors antagonists on the cell proliferation, viability, and VEGF secretion in pituitary lactosomatotroph GH3 cell culture in order to identify receptors involved in antiproliferative effects of angiotensins on GH3 tumor cells. Cell viability and proliferation using Mosmann method and BrdU incorporation during DNA synthesis, and VEGF secretion using ELISA assay were estimated. The inhibitory effects of ang II, ang IV, and ang 5-8 on the cell viability and BrdU incorporation in GH3 culture were not abolished by AT1, AT2, and AT4 receptors antagonists. Ang II, as well as ang III and ang IV at lower concentrations stimulated the secretion of VEGF in GH3 cell culture. The secretion of VEGF was inhibited by ang III and ang IV at higher concentrations. AT1 and AT2 receptors antagonists prevented the proangiogenic effects of ang II. Ang II, ang IV, and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1, AT2, and AT4 receptors. These peptides affect also secretion of VEGF in culture examined. Both the AT1 and AT2 receptors appear to mediate the proangiogenic effects of ang II.

Elevated peripheral blood plasma concentrations of tie-2 and angiopoietin 2 in patients with neuroendocrine tumors.

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.

Antineoplastic action of growth hormone-releasing hormone (GHRH) antagonists.

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.

Decreased 1-25 dihydroxyvitamin D3 concentration in peripheral blood serum of patients with thyroid cancer.

BACKGROUND AND AIMS: Vitamin D(3), in addition to its role in calcium homeostasis, has been recognized as playing a role in human cancer development. However, little is known about the association between vitamin D status and the development of thyroid cancer. This study aimed to investigate vitamin D metabolism by measuring 25(OH) D(3), 1-25 (OH)(2) D(3), PTH and calcium concentrations in the peripheral blood of patients with different forms of thyroid tumors. METHODS: The 25-hydroxyvitamin D(3) ,1-25- dihydoxyvitamin D(3), PTH and calcium serum levels of 50 consecutive patients with epithelial thyroid cancer 27 cases of papillary cancers (PTC), 16 follicular cancers (FTC), and seven cases of anaplastic cancers (ATC) and 34 multinodular nontoxic goiter (MNG) were measured by specific immunoassay. The control group consisted of 26 healthy volunteers. RESULTS: Our results revealed significantly lower 1-25 (OH)(2) D(3) concentration in the PTC group (22.67 pg/mL +/- 8.12; p <0.05), FTC group (16.09 pg/mL +/- 6.15; p <0.02) and ATC group (9.48 pg/mL +/- 5.18; p <0.02). Levels of 1-25 (OH)(2) D(3) varied by cancer stage and were also significantly different. A significant decrease in circulating 1-25 (OH)(2) D(3) concentration was found in patients with stage I (24.12 pg/mL +/- 6.77; p <0.05), stage II (16.93 pg/mL +/- 4.55; p <0.05), stage III (12.44 +/- 8.98; p <0.02) and in stage IVa (6.18 +/- 2.22; p <0.01). There were no significant differences when comparing serum levels of 25(OH) D(3), PTH or calcium concentrations among individuals with multinodular goiter, thyroid cancer and age- and sex-matched control volunteers. CONCLUSIONS: Our study revealed that impaired vitamin D(3) metabolism may play an important role in thyroid follicular cell oncogenesis.

Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro.

Several studies indicate the involvement of protein kinases in the progression of various malignancies. Kinase inhibitors are therefore becoming important anticancer drugs. CK2 kinase (casein kinase-2) has been suggested to be a constituent of a neoplastic milleu, and its inhibition might represent a new approach to cancer therapy. Adrenocortical carcinomas (ACCs) are highly malignant neoplasms with poor overall prognosis. We have examined the effects of 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), a potent CK2 inhibitor, on the H295R human adrenocortical cancer cell line. Treatment with DMAT decreases the secretion of aldosterone, dehydroepiandrosterone sulfate, and androstendione and results in an accumulation of 17-OH-progesterone. Cell growth as measured by the MTT and 5-bromo-2'-deoxyuridine incorporation assays is inhibited, and cell cycle analysis has revealed a slight induction of apoptosis. Thus, CK2 kinase activity is probably involved in human ACC endocrine activity and growth.

Growth hormone-releasing hormone stimulates the secretion of interleukin 17 from human peripheral blood mononuclear cells in vitro.

OBJECTIVES: Growth hormone-releasing hormone (GHRH) plays a crucial role in the secretion of GH from the pituitary, acts as a growth factor in variety of cancer cells and possesses immunomodulatory activity. Interleukin(IL)-17 apart from its pro-inflammatory role has been also shown to play a role in carcinogenesis. The effect of GHRH on the IL-17 has not been studied so far. AIM: To evaluate the effect of GHRH on the secretion of IL-17 from human peripheral blood mononuclear cells (PBMC) in vitro. MATERIALS AND METHODS: The concentrations of IL-17 in supernatants from PBMC cultured for 24 hrs were assessed using ELISA kit. RESULTS: We show for the first time that GHRH can stimulate the secretion of IL-17 from human PBMC in 24 hrs culture, and that GHRH antagonist counteracts this effect. CONCLUSION: Our study further elucidates the immunomodulatory role of GHRH.