Division of Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Radiat Oncol. 2017 Dec 29;12(1):208. doi: 10.1186/s13014-017-0939-0.
Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions.
Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O) vs. normoxic conditions (21% O). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi).
The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition.
Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.
缺氧诱导的放射抵抗是癌症治愈治疗的主要障碍。本研究旨在研究在缺氧条件下，光子和碳离子照射与 DNA 损伤反应（DDR）抑制剂联合对肿瘤细胞放射敏感性的影响。
用一系列光子和碳离子剂量对缺氧（1% O）与常氧（21% O）条件下的人非小细胞肺癌（NSCLC）模型 A549 和 H1437 进行照射。在双重放疗联合 DNA 依赖性蛋白激酶（DNAPKi，M3814）和 ATM 丝氨酸/苏氨酸激酶（ATMi）抑制剂后，研究克隆存活情况。
A549 细胞的光子照射 30%存活时 OER 为 1.4。A549 细胞 8 Gy 光子照射时，最大氧效应作为存活率为 2.34。相比之下，碳离子照射后没有发现明显的氧效应。因此，在常氧下，6 Gy 碳离子的相对效应为 3.8，在缺氧下为 4.11。ATM 和 DNA-PK 抑制剂剂量依赖性地增敏两种辐射质量的肿瘤细胞。在 100 nM DNAPKi 下，4 Gy 时的存活率从常氧下的 1.59 倍增至缺氧下的 3.3，表明在缺氧条件下具有很强的放射增敏作用。相比之下，在缺氧条件下，这种比值在光子照射和 ATMi 后仅中度增加。最有效的治疗方法是联合碳离子照射和 DNA 损伤修复抑制。
碳离子有效地消灭缺氧肿瘤细胞。ATMi 和 DNAPKi 均产生放射增敏作用。DNAPKi 优先增敏缺氧细胞的放射治疗。
