1 Radiation Biology Branch, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland.
2 National Institutes for Quantum and Radiological Science and Technology , Chiba, Japan .
Antioxid Redox Signal. 2018 Jan 10;28(2):131-140. doi: 10.1089/ars.2017.7106. Epub 2017 Sep 8.
Evofosfamide (TH-302) is a hypoxia-activated prodrug (HAP) that releases the DNA-damaging bromo-isophosphoramide mustard (Br-IPM) moiety selectively under hypoxic conditions. Since solid tumors are known to have hypoxic regions, HAPs in combination with chemotherapy or radiotherapy (XRT) will be beneficial. We tested the oxygen dependence of release kinetics of Br-IPM using electron paramagnetic resonance (EPR) with spin trapping by monitoring redox cycling of the nitroimidazole moiety of TH-302, and oxygen dependence of TH-302 on in vitro cytotoxicity at different levels of hypoxia was also examined. Two tumor implants (SCCVII and HT29) in mice were studied.
TH-302 fragmentation to release Br-IPM was noticed at oxygen levels <76 mmHg, which increased with higher levels of hypoxia. Enhanced cellular cytotoxicity was also observed at oxygen levels <76 mmHg. In vivo pO imaging in the two tumor implants showed that the SCCVII tumor implant had higher level of hypoxia compared with the HT29 xenograft. TH-302 as a monotherapy in vivo showed modest effects in SCCVII implants and minimal effects in HT29 xenografts, whereas TH-302 in combination with ionizing radiation showed significant benefit in both tumor models.
We examined the kinetics of redox cycling versus fragmentation of TH-302. The combination of oxygen-dependent XRT with TH-302 is effective even in tumors with significant hypoxia.
Imaging studies identifying the magnitude of hypoxia in tumors indicated that the responsiveness to TH-302 and the antitumor effect of TH-302 were enhanced by combining with XRT in both the TH-302-sensitive SCCVII tumor and -resistant HT29 tumor. Antioxid. Redox Signal. 28, 131-140.
依氟鸟氨酸（TH-302）是一种缺氧激活前药（HAP），在缺氧条件下选择性释放具有破坏 DNA 作用的溴代异磷酰胺（Br-IPM）部分。由于实体瘤已知存在缺氧区域，因此 HAP 联合化疗或放疗（XRT）将是有益的。我们使用电子顺磁共振（EPR）通过监测 TH-302 的硝基咪唑部分的氧化还原循环，测试了 Br-IPM 释放动力学的氧依赖性，并且还检查了不同缺氧水平下 TH-302 对体外细胞毒性的氧依赖性。在小鼠中研究了两种肿瘤植入物（SCCVII 和 HT29）。
在氧水平<76mmHg 时，注意到 TH-302 分裂以释放 Br-IPM，随着缺氧程度的增加而增加。在氧水平<76mmHg 时也观察到增强的细胞毒性。在两种肿瘤植入物中的体内 pO 成像显示，与 HT29 异种移植物相比，SCCVII 肿瘤植入物具有更高水平的缺氧。TH-302 作为单一疗法在体内对 SCCVII 植入物显示出适度的效果，对 HT29 异种移植物几乎没有效果，而 TH-302 与电离辐射联合使用在两种肿瘤模型中均显示出显著的益处。
我们检查了 TH-302 的氧化还原循环与分裂的动力学。即使在具有显著缺氧的肿瘤中，XRT 与氧依赖性结合也是有效的。
肿瘤中缺氧程度的成像研究表明，TH-302 与 XRT 联合使用增强了 TH-302 的敏感性和抗肿瘤作用，在 TH-302 敏感的 SCCVII 肿瘤和 -抗性 HT29 肿瘤中均如此。抗氧化。氧化还原信号。28,131-140。
