Introduction: Somatostatin and dopamine receptors have a pivotal role in control of hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the antitumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-dopamine chimera, in two human MTC cell lines. Methods: the effects of lanreotide (LAN) and TBR-065 on the cell growth proliferation, calcitonin secretion, cell cycle, apoptosis, cell migration and tumor-induced angiogenesis have been evaluated through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ECLIA assay, wound-healing assay and zebrafish platform, respectively. Results: TBR-065 exerted a more prominent antitumor activity compared to LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT: -50.3% and -37.6%, respectively; in MZ-CRC-1: -58.8% and -27%, respectively) and migration (in TT: -42.7% and -22.9%, respectively; in MZ-CRC-1: -75.5% and -58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT: -33.8%, MZ-CRC-1: -18.8%), and increased cells in G2/M phase (TT: +13%, MZ-CRC-1: +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect compared to LAN in TT cells. A concomitant decrease of calcitonin secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model. Discussion/Conclusion: In MTC cell lines a second generation somatostatin-dopamine analogue, TBR-065, exerts a more relevant anti-tumor activity, as compared with LAN, through modulation of cell cycle, induction of apoptosis and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo.


中文翻译：

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新型第二代生长抑素-多巴胺嵌合体 (TBR-065) 在人甲状腺髓样癌中的疗效：一项临床前研究

简介：生长抑素和多巴胺受体在控制包括甲状腺髓样癌 (MTC) 在内的不同神经内分泌肿瘤中的激素分泌和细胞增殖方面具有关键作用。在本临床前研究中，我们评估了第二代生长抑素-多巴胺嵌合体 TBR-065（原 BIM-23B065）在两种人类 MTC 细胞系中的抗肿瘤活性。方法：通过MTT法、碘化丙啶DNA流式细胞仪和Annexin评价兰瑞肽（LAN）和TBR-065对细胞生长增殖、降钙素分泌、细胞周期、凋亡、细胞迁移和肿瘤诱导血管生成的影响。 V-FITC/碘化丙啶染色、ECLIA 试验、伤口愈合试验和斑马鱼平台，分别。结果：与 LAN 相比，TBR-065 在两种 MTC 细胞系中都表现出更显着的抗肿瘤活性，如抑制细胞增殖所示（TT 中的最大抑制分别为 -50.3% 和 -37.6%；在 MZ-CRC-1 中：-58.8 % 和 -27%）和迁移（在 TT 中：分别为 -42.7% 和 -22.9%；在 MZ-CRC-1 中：分别为 -75.5% 和 -58.2%）。只有新嵌合体显着降低了S期细胞的比例（TT：-33.8%，MZ-CRC-1：-18.8%），增加了G2/M期细胞（TT：+13%，MZ-CRC- 1：+30.5%）。此外，与 LAN 相比，TBR-065 在 TT 细胞中发挥了更显着的促凋亡作用。与两种药物一起孵育 2 天后，观察到降钙素分泌同时减少，TBR-065 的效果更相关。然而，LAN 和 TBR-065 都没有对肿瘤诱导的血管生成产生任何影响，使用斑马鱼/肿瘤异种移植模型进行评估。讨论/结论：在 MTC 细胞系中，与 LAN 相比，第二代生长抑素-多巴胺类似物 TBR-065 通过调节细胞周期、诱导细胞凋亡和减少迁移发挥更相关的抗肿瘤活性。需要进一步的研究来确定 TBR-065 是否对体内肿瘤生长具有相当的有效抑制作用。