Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study

Florio, Tullio; Barbieri, Federica; Spaziante, Renato; Zona, Gianluigi; Hofland, Leo J.; Koetsveld, Peter M. van; Feelders, Richard A; Stalla, Günter; Theodoropoulou, Marily; Culler, Michael D.; Dong, Jesse Z.; Taylor, John E.; Moreau, Jacques-Pierre; Saveanu, Alexandru; Gunz, Ginette; Dufour, Henry; Jaquet, P

doi:10.1677/erc-07-0271

Cited by 97 publications

(100 citation statements)

References 59 publications

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“…The mean D 2 mRNA level was similar to that found in pituitary GH and gonadotroph tumors , Florio et al 2008) but was clearly higher than that of the GEP-NETs. Previous studies have shown the presence of D 2 in normal adrenal medulla and PCC by northern blot (Pupilli et al 1994, Wu et al 2001, by RT-PCR (Wu et al 2001), or by RT-PCR, immunohistochemistry, and ligand binding studies (Pivonello et al 2004).…”

Section: Discussionsupporting

confidence: 74%

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Saveanu¹,

Mureşan²,

Micco³

et al. 2011

Endocrine Related Cancer

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While somatostatin receptors (sst), through somatostatin-radiolabeled analogs, are used, mainly in second line, in the diagnosis and treatment of pheochromocytomas (PCC) and paragangliomas (PGL), the clinical significance of dopamine receptor subtype 2 (D 2 ) in PCC/PGL is unknown. Indeed, radiolabeled dopamine (DA) analogs such as fluorine 18 ( 18 F)-DA, used for positron emission tomography in PCC localization, are mainly correlated to the presence of noradrenaline transporter (NAT) and vesicular monoamine transporters (VMAT) but not to D 2 . The aim of this study was to quantitate D 2 and sst expression in 52 PCC/PGL and to compare it with that of 35 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Quantitative RT-PCR of sst 1-3 and sst 5 , D 2 , NAT, VMAT1/2 was performed in all tumors, while immunohistochemistry analysis of sst 2 and D 2 was performed in seven tumors. D 2 mRNA was expressed in all PCC/PGL. Mean expression was significantly higher in PCC/PGL than in GEP-NETs (4.8 vs 0.5 copy/copy b-glucuronidase (Gus)). sst 2 and sst 1 were expressed in most PCC/PGL, with sst 2 -dominant expression (mean mRNA: 1.6 vs 0.4 copy/copy b-Gus). sst 2 expression level was similar to that of GEP-NETs, whereas sst 5 expression level was significantly lower (0.12 vs 0.78 copy/copy b-Gus). Our study evidenced strong D 2 mRNA expression in PCC and for the first time in PGL. PCC/PGL express sst 2 mRNA at levels similar to those of GEP-NETs. New drugs can target ssts and D 2 more efficiently than current somatostatin analogs. Moreover, transporters like NAT and VMAT1/2, could be co-targeted with sst, as a basis of new radionuclide compounds in the imaging and treatment of these tumors.

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Section: Discussionsupporting

confidence: 74%

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Saveanu¹,

Mureşan²,

Micco³

et al. 2011

Endocrine Related Cancer

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“…SDF1 effect on cell proliferation was studied in eight primary cultures of human pituitary adenomas [two GHomas (GH1 and GH12), one ACTHoma (ACTH1), and five NFPAs (NFPA1, NFPA2, NFPA3, NFPA4, and NFPA6); see Supplementary Table S1B]. Experiments were carried out after magnetic fibroblast deprivation and isolated cells were grown in D-valine containing medium to assure a minimal fibroblast contamination (31). Immunofluorescence experiments done on isolated cells from one adenoma (GH2) showed that all the cells in culture, also expressing CXCR4 and SDF1, are derived from adenomatous tissue because they express GH but not procollagen type I (a marker for fibroblasts; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Single-cell suspensions were seeded (100,000 cells per well) in MEM with low glucose (1 g/L), containing D-valine (Metachem) to avoid fibroblast proliferation, supplemented with 10% FCS, penicillin/streptomycin, and 2.5 Ag/mL amphotericin B (Euroclone; ref. 31).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas

Barbieri¹,

Bajetto²,

Stumm

et al. 2008

Clinical Cancer Research

101

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Purpose: Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell^derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation. Experimental Design: The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures. Results: CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone^secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin. Conclusions: CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development 'in humans.

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“…Thus, dopamine agonists (DA) reduce gonadotropin secretion (14) and inhibit thymidine incorporation in vitro (15), providing a potential therapeutic target for NFPA. However, dopaminergic binding sites (16) as well as D2R mRNA isoforms (17) are less abundant in NFPA than in prolactinomas, perhaps accounting for the modest rate of tumor shrinkage attained by DAs (18).…”

Section: Introductionmentioning

confidence: 99%

Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists

Greenman

Cooper

Yaish

et al. 2016

European Journal of Endocrinology

118

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Objective: Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. Design: The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. Methods: Seventy-nine patients followed for 8.8 ± 6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n = 55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n = 24). The control group (n = 60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. Results: Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001. Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P < 0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P = 0.002). Outcome measures were not related to NFPA D2R abundance. Conclusions: Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

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Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study

Cited by 97 publications

References 59 publications

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas

Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists

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