Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas - Novel potential therapy for functional pituitary tumors
Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas - Novel potential therapy for functional pituitary tumors
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DOI：
10.1172/jci119779
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发表时间：
1997-11-01
影响因子：
15.9
通讯作者：
Melmed, S
中科院分区：
文献类型：
--
作者：
Shimon, I;Yan, XM;Melmed, S
以前，我们已经表明生长抑素受体（SSTR）亚型特异性调节生长激素（GH），促甲状腺激素和催乳素（PRL）分泌在人胎儿垂体培养，其中GH和促甲状腺激素介导的SSTR 2和SSTR 5，而SSTR 2优先介导PRL分泌。我们现在测试SSTR亚型选择性类似物在原代人GH和PRL分泌型垂体腺瘤培养。在稳定表达人SSTR形式的细胞中通过膜放射性配体结合测定的抗肿瘤亲和力是SSTR 2或SSTR 5选择性的。对SSTR 2具有优先选择性的类似物，包括奥曲肽、兰瑞肽和对SSTR 2具有改善的亲和力的新化合物，或新的SSTR 5选择性化合物在肿瘤细胞培养物中抑制GH（高达对照的44%; P < 0.0005）。然而，两组的新类似物在抑制GH方面比奥曲肽和兰瑞肽强30-40%（P < 0.05）。含有SSTR 2-和SSTR 5-选择性化合物的杂环类似物组合在降低GH方面比单独使用的类似物（P < 0.05）或比对相同受体亚型特异性的化合物的组合（P < 0.005）更有效。与此相反，SSTR 2选择性类似物没有抑制PRL释放从六个培养的泌乳素瘤研究。然而，新的SSTR 5选择性类似物在6个泌乳素瘤中的4个中抑制了体外PRL分泌（30-40%; P < 0.05）。这些结果表明，SSTR 2和SSTR 5参与生长激素腺瘤细胞的GH调节，而SSTR 5专门调节泌乳素腺瘤细胞的PRL分泌。因此，生长抑素类似物与这些受体亚型的选择性结合亲和力的改善可能是有效的GH或PRL分泌腺瘤的治疗。
Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH-and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH-or PRL-secreting adenomas.