Department of Radiation Oncology, David Geffen School of Medicine at UCLA, United States.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, United States.
Radiother Oncol. 2024 Dec;201:110562. doi: 10.1016/j.radonc.2024.110562. Epub 2024 Sep 27.
Dopamine receptor antagonists have recently been identified as potential anti-cancer agents in combination with radiation, and a first drug of this class is in clinical trials against pediatric glioma. Radiotherapy causes cognitive impairment primarily by eliminating neural stem/progenitor cells and subsequent loss of neurogenesis, along with inducing inflammation, vascular damage, and synaptic alterations. Here, we tested the combined effects of dopamine receptor antagonists and radiation on neural stem/progenitor cells.
Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of EGFP, the effects of dopamine receptor antagonists alone or in combination with radiation on neural stem/progenitor cells were assessed in sphere-formation assays, extreme limiting dilution assays, flow cytometry and real-time PCR in vitro and in vivo in both sexes.
We report that hydroxyzine and trifluoperazine exhibited sex-dependent effects on murine newborn neural stem/progenitor cells in vitro. In contrast, amisulpride, nemonapride, and quetiapine, when combined with radiation, significantly increased the number of neural stem/progenitor cells in both sexes. In vivo, trifluoperazine showed sex-dependent effects on adult neural stem/progenitor cells, while amisulpride demonstrated significant effects in both sexes. Further, amisulpride increased sphere forming capacity and stem cell frequency in both sexes when compared to controls.
We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exists, making it a novel combination therapy against glioblastoma. Normal tissue toxicity following this treatment scheme likely differs depending on age and sex and should be taken into consideration when designing clinical trials.
多巴胺受体拮抗剂最近被确定为与放射治疗联合使用的潜在抗癌药物，该类药物中的第一种正在针对小儿脑胶质瘤进行临床试验。放射治疗主要通过消除神经干细胞/祖细胞以及随后的神经发生丧失、诱导炎症、血管损伤和突触改变导致认知障碍。在这里，我们测试了多巴胺受体拮抗剂与放射治疗对神经干细胞/祖细胞的联合作用。
使用通过巢蛋白启动子驱动 EGFP 表达报告神经干细胞/祖细胞存在的转基因小鼠，通过球体形成测定、极限稀释测定、流式细胞术和实时 PCR，在体外和体内（雌雄两性）评估多巴胺受体拮抗剂单独或与放射治疗联合对神经干细胞/祖细胞的作用。
我们报告称，羟嗪和三氟拉嗪在体外对新生雄性和雌性小鼠神经干细胞/祖细胞表现出性别依赖性作用。相比之下，阿米舒必利、奈莫必利和喹硫平与放射治疗联合使用时，显著增加了雌雄两性的神经干细胞/祖细胞数量。在体内，三氟拉嗪对成年神经干细胞/祖细胞表现出性别依赖性作用，而阿米舒必利在雌雄两性中均表现出显著作用。此外，与对照组相比，阿米舒必利增加了两性的球体形成能力和干细胞频率。
我们得出结论，多巴胺受体拮抗剂与放射治疗联合治疗存在治疗窗口，这使其成为治疗神经胶质瘤的一种新的联合治疗方法。在设计临床试验时，应考虑到这种治疗方案对正常组织的毒性，这可能因年龄和性别而异。
