Liapis Vasilios, Zinonos Irene, Labrinidis Agatha, Hay Shelley, Ponomarev Vladimir, Panagopoulos Vasilios, Zysk Aneta, DeNichilo Mark, Ingman Wendy, Atkins Gerald J, Findlay David M, Zannettino Andrew C W, Evdokiou Andreas
Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, Woodville, South Australia, Australia.
Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Med. 2016 Mar;5(3):534-45. doi: 10.1002/cam4.599. Epub 2016 Jan 9.
Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. Evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth. Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. Evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.
肿瘤缺氧是多种恶性肿瘤治疗失败的主要原因。然而，缺氧也提供了治疗机会，以靶向肿瘤内缺氧区域的化合物的开发为例。依沃福酰胺（TH - 302）是一种前药，由2 - 硝基咪唑与溴异磷酰胺芥（Br - IPM）偶联而成。当依沃福酰胺被输送到缺氧区域时，DNA交联效应物Br - IPM被释放。本研究评估了依沃福酰胺在体外的细胞毒性活性及其在体内单独或与紫杉醇联合对溶骨性乳腺癌的抗肿瘤活性。在缺氧条件下用依沃福酰胺处理一组人乳腺癌细胞系，并评估细胞活力。将溶骨性MDA - MB - 231 - TXSA细胞移植到小鼠乳腺脂肪垫或胫骨中，待其定植后用依沃福酰胺、紫杉醇或两者进行处理。使用生物发光监测肿瘤负荷，使用微型计算机断层扫描（micro - CT）测量癌症诱导的骨破坏。在体外，依沃福酰胺在缺氧条件下具有选择性细胞毒性。在体内，依沃福酰胺作为单一药物具有肿瘤抑制作用，并与紫杉醇协同作用以减少乳腺肿瘤生长。移植到小鼠胫骨中的乳腺癌细胞形成了溶骨性病变。相比之下，用依沃福酰胺或紫杉醇治疗导致肿瘤生长显著延迟，骨内肿瘤负荷总体降低，而联合治疗导致小鼠胫骨肿瘤负荷显著更大程度的降低。依沃福酰胺与紫杉醇协同作用，对乳腺和骨中的乳腺癌生长表现出强大的肿瘤抑制活性。
