Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer.
背景/目的：脑癌的治疗仍然面临挑战，数十年来生存率未见显著改善。胶质母细胞瘤的耐药性极大地制约了传统放射治疗的疗效。然而，高剂量率放疗具有独特优势，能在控制肿瘤的同时保护正常组织。联合使用靶向放射增敏剂，如化疗药物甲氨蝶呤（MTX）或高原子序数卤化嘧啶类药物碘脱氧尿苷（IUdR），可进一步提升放疗效果。将这些放射增敏剂与超高剂量率（UHDR）同步辐射X射线相结合，可能产生协同效应，从而增强这种多模式UHDR疗法的疗效，为克服脑癌的放射抵抗性提供新途径。 方法：本研究采用处理后受控的体外实验方法，包括通过克隆形成实验测定长期细胞存活率，以及利用γH2AX免疫荧光共聚焦显微镜技术定量检测DNA双链断裂（DSBs）。 结果：研究发现，IUdR与MTX联合同步辐射X射线治疗可产生高度协同的显著增强效应。细胞存活实验表明，在相同5 Gy剂量下，联合使用这两种药物与UHDR同步辐射X射线相比仅使用传统X射线，对9L胶质肉瘤细胞的杀伤效果提高了5.4倍。通过γH2AX成像技术揭示其内在机制，结果显示暴露于UHDR辐射后，DNA双链断裂和死亡细胞数量显著增加。 结论：本研究证实，与传统放疗相比，采用UHDR同步辐射的高度协同联合治疗方案能显著提升脑癌细胞杀伤效果。我们预期这种具有叠加效应的多模式联合疗法将为未来脑癌治疗提供更精准、更有效的放疗选择方案。
Combinational Radiotherapies Improve Brain Cancer Treatment at High Dose Rates In Vitro
肿瘤(癌症)患者之家