Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models.
Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models.
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DOI：
10.18383/j.tom.2016.00259
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Quarles CC
中科院分区：
文献类型：
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作者：
Stokes AM;Hart CP;Quarles CC
高级别胶质瘤通常以缺氧为特征，这与不良的长期预后和治疗抵抗有关。缺氧在治疗抵抗和疾病进展中所起的不利作用导致了缺氧成像方法和缺氧靶向治疗的发展。在这里，我们使用 18-氟米索硝唑正电子发射断层扫描确定了 2 个大鼠原位胶质瘤模型的肿瘤缺氧和血管灌注特征。此外，我们还在这些大鼠神经胶质瘤模型中确定了肿瘤对缺氧激活的前药依福磷酰胺 (TH-302) 的反应。 C6 肿瘤比 9L 肿瘤表现出更多的缺氧和更少的灌注。基于肿瘤缺氧负荷的这些差异，evofosfamide 治疗导致 C6 和 9L 肿瘤的肿瘤生长率分别降低 4 倍和 2 倍。这项工作表明，对肿瘤缺氧和灌注敏感的成像方法能够预测对缺氧靶向药物的反应。这对于改善患者选择具有重要意义，特别是在临床试验中，使用缺氧激活的细胞毒性前药（例如依佛磷酰胺）进行治疗。
High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide.