Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones Cientificas y Técnicas, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina.
Endocrinology. 2012 Aug;153(8):3861-71. doi: 10.1210/en.2012-1007. Epub 2012 Jun 14.
Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.
催乳素瘤是人类最常见的分泌性垂体肿瘤，通常对多巴胺激动剂的药物治疗反应良好。然而，对于对多巴胺能药物有抗药性的患者，需要寻求替代治疗方法。抗血管生成策略可能是这些肿瘤的潜在治疗方法。血小板反应蛋白 1（TSP-1）是一种参与多种生物学过程的大型多功能糖蛋白，包括血管生成、细胞凋亡和 TGF-β1 的激活。由于过度表达 TSP-1 的肿瘤生长速度较慢，转移较少，血管生成减少，因此 TSP-1 为癌症治疗提供了一个新的靶点。ABT-510 和 ABT-898 是 TSP-1 的合成类似物，可模拟其抗血管生成作用。在本研究中，我们探讨了 AB T-510 和 ABT-898 对慢性己烯雌酚（DES）处理诱导的雌性大鼠实验性催乳素瘤的潜在作用。我们证明，ABT-510 和 ABT-898 的 2 周治疗可对抗 DES 诱导的垂体大小和血清催乳素水平以及垂体增殖率的增加。这些对肿瘤生长的抑制作用可能是由药物的抗血管生成特性介导的。我们还证明，ABT-510 和 ABT-898 除了具有描述的抗血管生成作用外，还增加了肿瘤中活性 TGF-β1 的水平。我们假设局部细胞因子激活的恢复参与了催乳素细胞功能的抑制。这些结果将这些合成的 TSP-1 类似物作为多巴胺激动剂抵抗性催乳素瘤的潜在替代或补充治疗方法。
