期刊
PITUITARY
卷 24, 期 3, 页码 351-358出版社
SPRINGER
DOI: 10.1007/s11102-020-01113-4
关键词
Acromegaly; Dopastatin; Octreotide; Cabergoline; TBR-065
资金
- IPSEN research grant
- Centre National de la Recherche Scientifique (CNRS UMR)
- Institut National de la Sante et de la Recherche Medicale (INSERM) Aix Marseille University
- Association pour le Developpement et la Recherche Medicales (ADEREM)
- Excellence Initiative of Aix Marseille University A*Midex-a French Investissement d'Avenir
The chimeric compound TBR-065, a second-generation dopastatin, shows significantly improved efficacy in suppressing GH secretion compared to current therapies, indicating a promising new option for the treatment of acromegaly.
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. M 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 mu M) 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-max = 57 +/- 5.6% vs. 41.1 +/- 12.5%, respectively, p < 0.001) or with OCT + CAB (E-max = 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.
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