a Radiation Non-clinic Center, Korea Institute of Radiological & Medical Sciences , Seoul , Korea.
b Department of Radiation Oncology , Korea Institute of Radiological & Medical Sciences , Seoul , Korea.
Int J Hyperthermia. 2018 May;34(3):276-283. doi: 10.1080/02656736.2017.1335440. Epub 2017 Jun 28.
Mild temperature hyperthermia (MTH) increases blood flow and oxygenation in tumours. On the other hand, high-dose-per-fraction irradiation damages blood vessels, decreases blood flow and increases hypoxia in tumours. The radiation-induced hypoxia in tumours activates hypoxia-inducible factor-1α (HIF-1α) and its target genes, such as vascular endothelial growth factor (VEGF), promoting revascularization and recurrence. In the present study, we examined the hypothesis that MTH inhibits radiation-induced upregulation of HIF-1α and its target genes by increasing tumour oxygenation.
FSaII fibrosarcoma tumours grown subcutaneously in the legs of C3H mice were used. Tumours were irradiated with 15 Gy using a Co irradiator or heated at 41 °C for 30 min using an Oncothermia heating unit. Blood perfusion and hypoxia in tumours were assessed with Hoechst 33342 and pimonidazole staining, respectively. Expression levels of HIF-1α and VEGF were determined using immunohistochemical techniques. Apoptosis of tumour cells was quantitated via TUNEL staining and the effects of treatments on tumour growth rate were assessed by measuring tumour diameters.
Irradiation of FSaII tumours with a single dose of 15 Gy led to significantly decreased blood perfusion, increased hypoxia and upregulation of HIF-1α and VEGF. On the other hand, MTH at 41 °C for 30 min increased blood perfusion and tumour oxygenation, thereby suppressing radiation-induced HIF-1α and VEGF in tumours, leading to enhanced apoptosis of tumour cells and tumour growth delay.
MTH enhances the anti-tumour effect of high-dose irradiation, at least partly by inhibiting radiation-induced upregulation of HIF-1α.
轻度体温升高（MTH）可增加肿瘤中的血液流量和氧合作用。另一方面，高剂量分次照射会破坏血管，减少血液流量并增加肿瘤中的缺氧。肿瘤中的辐射诱导缺氧会激活缺氧诱导因子-1α（HIF-1α）及其靶基因，如血管内皮生长因子（VEGF），从而促进血管新生和复发。在本研究中，我们检验了以下假设，即 MTH 通过增加肿瘤氧合作用来抑制辐射诱导的 HIF-1α及其靶基因的上调。
使用皮下生长在 C3H 小鼠腿部的 FSaII 纤维肉瘤肿瘤。使用 Co 辐照仪对肿瘤进行 15Gy 的照射，或使用 Oncothermia 加热装置将肿瘤加热至 41°C 30 分钟。使用 Hoechst 33342 和 pimonidazole 染色分别评估肿瘤中的血液灌注和缺氧。使用免疫组织化学技术确定 HIF-1α 和 VEGF 的表达水平。通过 TUNEL 染色定量测定肿瘤细胞的凋亡，并通过测量肿瘤直径来评估治疗对肿瘤生长速率的影响。
单次给予 15Gy 的剂量照射 FSaII 肿瘤会导致血液灌注明显减少、缺氧增加以及 HIF-1α 和 VEGF 的上调。另一方面，41°C 30 分钟的 MTH 可增加血液灌注和肿瘤氧合作用，从而抑制肿瘤中辐射诱导的 HIF-1α 和 VEGF，导致肿瘤细胞凋亡增加和肿瘤生长延迟。
MTH 增强了高剂量照射的抗肿瘤作用，至少部分是通过抑制辐射诱导的 HIF-1α 的上调。
