第二代生长抑素-多巴胺受体嵌合分子TBR-065抑制人生长激素分泌性腺瘤细胞分泌生长激素能力的表征。

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells.

作者信息

Cuny Thomas, Graillon Thomas, Defilles Célines, Datta Rakesh, Zhang Shengwen, Figarella-Branger Dominique, Dufour Henry, Mougel Grégory, Brue Thierry, Landsman Tanya, Halem Heather A, Culler Michael D, Barlier Anne, Saveanu Alexandru

机构信息

Service d'Endocrinologie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Conception, 147 Boulevard Baille, 13005, Marseille, France.

Service de Neurochirurgie, Aix Marseille University, APHM, Marseille Medical Genetics, Inserm U1251, Hôpital de la Timone, Marseille, France.

出版信息

Pituitary. 2021 Jun;24(3):351-358. doi: 10.1007/s11102-020-01113-4. Epub 2021 Jan 12.

DOI:10.1007/s11102-020-01113-4

PMID:33433890

Abstract

CONTEXT

Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined).

OBJECTIVE

To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas.

DESIGN

We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures.

METHODS

17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h.

RESULTS

All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (E = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (E = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065.

CONCLUSION

TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.

摘要

背景

生长抑素（SST）和多巴胺（DA）通过与SSTR2和D2R受体结合，抑制生长激素（GH）分泌及生长激素分泌型垂体腺瘤（GH瘤）的增殖。与单独的SST或DA类似物（单独使用或联合使用）相比，嵌合型SST-DA化合物（多巴胺抑素）在抑制GH分泌方面表现出更高的效力。

目的

评估第二代多巴胺抑素TBR-065对抑制人GH瘤和GH/泌乳素（PRL）瘤分泌GH的疗效。

设计

我们比较了TBR-065与第一代多巴胺抑素TBR-760（原名BIM-23A760）、奥曲肽（OCT）和卡麦角林（CAB）（单独使用或联合使用）对人GH瘤或GH/PRL瘤细胞原代培养物中GH分泌的抑制能力。我们研究了TBR-065的代谢产物BIM-133对这些培养物中TBR-065抑制GH能力的影响。

方法

本研究纳入了17个GH瘤和GH/PRL瘤。在8小时内评估TBR-065、TBR-760、OCT和CAB（0.1 pM至0.1 μM）对GH分泌的抑制作用。

结果

所有肿瘤均表达SSTR2和D2R mRNA。与TBR-760相比，TBR-065对GH的抑制作用更强（分别为E = 57 ± 5.6% 对41.1 ± 12.5%，p < 0.001），与OCT + CAB相比也是如此（E = 56.8 ± 7.2% 对44.4 ± 9.4%，p < 0.001）。BIM-133对TBR-065的活性没有任何影响。