缺氧诱导因子通路抑制可解决肿瘤缺氧问题，并在单次照射后改善局部肿瘤控制。

Hypoxia-inducible factor pathway inhibition resolves tumor hypoxia and improves local tumor control after single-dose irradiation.

机构信息

OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

出版信息

Int J Radiat Oncol Biol Phys. 2014 Jan 1;88(1):159-66. doi: 10.1016/j.ijrobp.2013.09.047.

DOI:10.1016/j.ijrobp.2013.09.047

PMID:24331663

Abstract

PURPOSE

To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors.

METHODS AND MATERIALS

UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD50) was calculated.

RESULTS

BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD50, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD50.

CONCLUSIONS

BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation.

摘要

目的

研究新型口服生物可利用的线粒体复合物 I 和低氧诱导因子 1（HIF-1）活性抑制剂 BAY-84-7296 对肿瘤缺氧、微环境和放射反应的影响。

方法与材料

将 UT-SCC-5 和 UT-SCC-14 人鳞状细胞癌皮下移植到裸鼠中。当肿瘤直径达到 4 毫米时，每日给予 BAY-84-7296（拜耳制药公司）或载体。在 7 毫米的肿瘤时，将其切除进行 Western blot 和免疫组织化学研究，或进行单次照射。照射后，动物随机接受 BAY-84-7296 维持或载体治疗。照射后 150 天评估局部肿瘤控制情况，并计算肿瘤控制 50%的剂量（TCD50）。

结果

BAY-84-7296 降低了核 HIF-1α 的表达。大约 2 周的抑制剂每日给药导致 UT-SCC-5 中 pimonidazole 低氧分数明显下降（0.5%比 21%，P<.0001），UT-SCC-14 中下降（0.3%比 19%，P<.0001）。这种减少伴随着 UT-SCC-14 中灌注血管比例的显著增加，但在 UT-SCC-5 中没有。溴脱氧尿苷和 Ki67 标记指数仅在 UT-SCC-5 中显著降低。血管面积或坏死没有明显变化。单次照射前的 BAY-84-7296 显著降低了 TCD50，UT-SCC-5 中的增强比为 1.37（95%置信区间 [CI] 1.13-1.72），UT-SCC-14 中的增强比为 1.55（95%置信区间 [CI] 1.26-1.94）。照射后 BAY-84-7296 的维持并没有进一步降低 TCD50。