Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Research Institute, Shiga Medical Center, Shiga, Japan.
PLoS One. 2023 Mar 16;18(3):e0279634. doi: 10.1371/journal.pone.0279634. eCollection 2023.
Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke's cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke's cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-β (PDGFR-β)-positive cells, which suggests that capillaries around Rathke's cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke's cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.
抗血管内皮生长因子（VEGF）治疗已被开发用于治疗多种癌症。虽然这种治疗方法可能是治疗难治性垂体腺瘤和垂体癌的有前途的替代治疗方法，但抗 VEGF 药物对垂体的作用尚不清楚。在这里，我们发现接受 OSI-930 治疗的小鼠（一种包括 VEGF 受体 1 和 2 的受体酪氨酸激酶抑制剂）经常在垂体中出现出血。这是第一个报道抗 VEGF 治疗可引起垂体卒中的报告。C57BL/6 小鼠每天腹膜内注射 100mg/kg 体重的 OSI-930，持续 1 至 6 天。用免疫组织化学方法检查垂体。在接受三天治疗的六只小鼠中有四只和接受六天治疗的五只小鼠中有五只在垂体中出现出血。在所有情况下，出血都发生在 Rathke 裂附近。在 OSI-930 给药的小鼠中，在前叶中血管覆盖和分支减少，并且毛细血管网络也在中间叶中以治疗天数依赖的方式减少。在中间叶的 Rathke 裂周围，很少有血管表达 VE-钙粘蛋白，并且血小板衍生生长因子受体-β（PDGFR-β）阳性细胞覆盖。这表明中间叶 Rathke 裂周围的毛细血管是 VE-钙粘蛋白阴性的，并且没有周细胞覆盖。在发生出血的部位观察到 Rathke 裂周围毛细血管丛的减少，这表明与垂体出血的发病机制有关。我们的研究表明，抗 VEGF 药物有发生垂体卒中的风险。应将垂体卒中作为抗 VEGF 治疗的不良反应加以注意。
