Kumar Sushil, Sun Jessica D, Zhang Libo, Mokhtari Reza Bayat, Wu Bing, Meng Fanying, Liu Qian, Bhupathi Deepthi, Wang Yan, Yeger Herman, Hart Charles, Baruchel Sylvain
Division of Hematology and Oncology, Hospital for Sick Children, 686 Bay St, Toronto, ON, Canada, M5G 0A4; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Room 2374, Toronto, Ontario, Canada, M5S 1A8.
Threshold Pharmaceuticals Inc., 170 Harbor Way # 300, South San Francisco, CA, USA, 94080.
Transl Oncol. 2018 Aug;11(4):911-919. doi: 10.1016/j.tranon.2018.05.004. Epub 2018 May 31.
Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other.
抗血管生成疗法在临床前和临床试验中已显示出有前景的结果。然而，肿瘤细胞通过获得在抗血管生成疗法诱导的缺氧条件下存活和增殖的能力，从而对该疗法产生抗性。将抗血管生成疗法与缺氧激活前体药物联合使用可以克服这一局限性。在此，我们测试了抗血管生成药物舒尼替尼与缺氧激活前体药物依沃福酰胺联合用于神经母细胞瘤的效果。在体外，与常氧条件相比，神经母细胞瘤细胞系SK-N-BE(2)在缺氧条件下对依沃福酰胺的敏感性高40倍。在IV期转移模型中，与赋形剂相比，依沃福酰胺显著提高了小鼠存活率（P = 0.02）。在SK-N-BE(2)皮下异种移植模型中，我们使用30mg/kg舒尼替尼和50mg/kg依沃福酰胺测试了两种不同的治疗方案。在此，在皮下SK-N-BE(2)异种移植模型中，舒尼替尼与依沃福酰胺同时开始治疗时，与单一药物相比显示出更高的疗效，而舒尼替尼在依沃福酰胺治疗7天后开始使用时，与单一药物治疗相比没有任何优势。肿瘤切片的免疫荧光显示，当两种治疗同时开始时，与单一药物相比，凋亡细胞数量和缺氧区域更多。在异种移植和转移模型中，80mg/kg舒尼替尼与50mg/kg依沃福酰胺联合治疗均显著优于单一药物。本研究证实了舒尼替尼和依沃福酰胺在侵袭性神经母细胞瘤小鼠模型中的临床前疗效。舒尼替尼通过增加缺氧区域来增强依沃福酰胺的疗效，而依沃福酰胺靶向缺氧肿瘤细胞。因此，每种药物都增强了另一种药物的活性。
