Nishri Yossi, Vatarescu Maayan, Luz Ishai, Epstein Lior, Dumančić Mirta, Del Mare Sara, Shai Amit, Schmidt Michael, Deutsch Lisa, Den Robert B, Kelson Itzhak, Keisari Yona, Arazi Lior, Cooks Tomer, Domankevich Vered
Translational Research Laboratory, Alpha Tau Medical, Jerusalem, Israel.
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
Front Oncol. 2022 Sep 27;12:888100. doi: 10.3389/fonc.2022.888100. eCollection 2022.
Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.
多形性胶质母细胞瘤（GBM）目前是一种无法治愈的疾病，尽管手术、放射治疗、化疗[如替莫唑胺（TMZ）]和靶向治疗[如抗血管生成剂贝伐单抗（BEV）]等治疗方式有所改进，但其5年生存率仍为5.5%。扩散性α粒子放射治疗（DaRT）是一种新的治疗方式，它使用装载镭-224的种子，使α发射原子在肿瘤内扩散。这种治疗方法在携带人源GBM肿瘤的小鼠中显示出有效性。在此，研究了DaRT与TMZ或BEV等标准治疗方法联合使用的效果。在生存能力测定中，α辐射与TMZ联合使用使U87培养细胞中每种治疗单独使用时的细胞毒性作用增加了一倍。集落形成试验表明，TMZ联合α照射处理的U87细胞存活分数低于α射线或X射线单一疗法，或X射线联合TMZ所达到的存活分数。用DaRT和TMZ治疗携带U87肿瘤的小鼠比单一疗法更能延缓肿瘤发展。与其他辐射类型不同，α辐射不会增加培养的U87细胞中VEGF的分泌。在DaRT植入几天后进行BEV治疗，与BEV或DaRT单一疗法相比，改善了肿瘤控制。在相对于种子大小的大肿瘤中，在DaRT植入前开始给予BEV时，该联合治疗也显示出优越性。在DaRT治疗下，BEV诱导CD31染色减少，增加了镭子代原子在肿瘤组织中的扩散，并减少了它们通过血液从肿瘤中的清除。综上所述，DaRT与标准护理化疗或抗血管生成治疗的联合使用是有前景的方法，可能改善GBM患者的治疗。
