OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
J Transl Med. 2023 Aug 26;21(1):576. doi: 10.1186/s12967-023-04439-2.
Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use.
Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined.
Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC.
Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.
肿瘤缺氧与放射治疗和化学治疗的耐药性有关。在头颈部鳞状细胞癌（HNSCC）中，氧模拟物尼莫唑联合放射治疗（RT）能够改善一些缺氧肿瘤患者的局部区域控制（LRC），但尚不清楚这是否也适用于放化疗（RCTx）。在这里，我们研究了尼莫唑联合 RCTx 在 HNSCC 异种移植中的影响，并探索了其靶向应用的分子生物标志物。
在 6 周内进行 30 次分割照射，联合每周顺铂。尼莫唑在每次分割前应用，从第一次或第十次分割开始。RCTx 加或不加尼莫唑的效果通过照射后永久性局部控制来量化。对于组织学评估和靶向基因表达分析，未经处理或在接受十次分割后切除肿瘤。使用定量图像分析确定微环境参数。
尼莫唑联合 RCTx 显著改善了两种肿瘤模型的永久性局部控制，并在另外两种模型中显示出潜在的改善。在这四种模型中，单独进行 RCTx 十次分割后，pimonidazole 缺氧体积（pHV）显著减少。我们的结果表明，如果在 RCTx 过程中缺氧减少，尼莫唑联合 RCTx 可能比 RCTx 单独治疗更能改善 TCR，但需要进一步的实验来验证这种关联。差异基因表达分析显示 12 个基因可能与 RCTx 反应有关。当评估接受原发性 RCTx 治疗的 HNSCC 患者时，这些基因对 LRC 具有预测作用。
尼莫唑联合 RCTx 改善了一些但不是所有 HNSCC 异种移植的局部肿瘤控制。我们鉴定了具有转化为 HNSCC 患者潜力的预后生物标志物。
