Valceski Michael, Engels Elette, Vogel Sarah, Paino Jason, Potter Dylan, Hollis Carolyn, Khochaiche Abass, Barnes Micah, O'Keefe Alice, Cameron Matthew, Roughley Kiarn, Rosenfeld Anatoly, Lerch Michael, Corde Stéphanie, Tehei Moeava
Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW 2522, Australia.
Building 42 Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia.
Cancers (Basel). 2025 May 20;17(10):1713. doi: 10.3390/cancers17101713.
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.
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).
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.
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：脑癌的治疗仍然困难重重，数十年来生存率统计一直停滞不前。胶质母细胞瘤对传统癌症放疗的抗性极大地挑战了其有效性。然而，高剂量率放疗具有独特的效果，能够在维持肿瘤控制的同时保护正常组织。添加靶向放射增敏剂，如化疗药物甲氨蝶呤（MTX）或高Z值卤代嘧啶药物碘脱氧尿苷（IUdR），可以改善放疗效果。将这些放射增敏剂与超高剂量率（UHDR）同步加速器X射线相结合，可产生协同效应，提高这些多模态UHDR疗法的疗效，为克服脑癌的放射抗性提供一种手段。
在此，我们在治疗后使用了体外对照试验，包括克隆形成试验以确定长期细胞存活率，以及γH2AX免疫荧光共聚焦显微镜来量化双链DNA断裂（DSB）。
我们发现IUdR + MTX与同步加速器X射线的高度协同组合有显著增强效果。细胞存活结果表明，在相同5 Gy剂量下，与单独使用传统X射线相比，当这些药物与UHDR同步加速器X射线联合使用时，9L胶质肉瘤细胞的杀伤率提高了5.4倍。使用γH2AX成像揭示了潜在机制，并显示在暴露于UHDR辐射后DSB和死亡细胞显著增加。
我们的结果表明，与传统放疗相比，使用UHDR同步加速器辐射的高度协同联合治疗可显著提高脑癌的杀伤效果。我们预计，这些附加的多模态联合疗法将为未来脑癌治疗中更有针对性和有效地使用放疗提供选择。
