Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Woodville, South Australia, Australia.
Vascular Biology and Cell Trafficking Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Cancer Med. 2017 Sep;6(9):2164-2176. doi: 10.1002/cam4.1115. Epub 2017 Aug 10.
Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to the cytotoxic bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions of tumors, the DNA cross-linking toxin, Br-IPM, is released leading to cell death. This study assessed the anticancer efficacy of evofosfamide in combination with the Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab against human osteosarcoma in vitro and in an intratibial murine model of osteosarcoma. Under hypoxic conditions in vitro, evofosfamide cooperated with dulanermin and drozitumab, resulting in the potentiation of cytotoxicity to osteosarcoma cells. In contrast, under the same conditions, primary human osteoblasts were resistant to treatment. Animals transplanted with osteosarcoma cells directly into their tibiae developed mixed osteosclerotic/osteolytic bone lesions and consequently developed lung metastases 3 weeks post cancer cell transplantation. Tumor burden in the bone was reduced by evofosfamide treatment alone and in combination with drozitumab and prevented osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. These results suggest that evofosfamide may be an attractive therapeutic agent, with strong anticancer activity alone or in combination with either drozitumab or dulanermin against osteosarcoma.
肿瘤缺氧是多种恶性肿瘤治疗失败的主要原因。然而，缺氧也为治疗提供了机会，例如开发针对肿瘤缺氧区域的化合物。依氟鸟氨酸是一种缺氧激活的前药，它通过将缺氧寻找的 2-硝基咪唑部分与细胞毒性溴代异磷酰胺（Br-IPM）连接而形成。当依氟鸟氨酸被递送到肿瘤的缺氧区域时，释放出 DNA 交联毒素 Br-IPM，导致细胞死亡。本研究评估了依氟鸟氨酸与促凋亡受体激动剂（PARAs）杜拉明和 drozitumab 联合治疗体外人骨肉瘤和骨肉瘤的胫骨内鼠模型的抗癌疗效。在体外缺氧条件下，依氟鸟氨酸与杜拉明和 drozitumab 协同作用，增强了对骨肉瘤细胞的细胞毒性。相比之下，在相同条件下，原代人成骨细胞对治疗具有抗性。将骨肉瘤细胞直接移植到胫骨中的动物会在癌症细胞移植后 3 周发展为混合成骨硬化/溶骨性骨病变，并因此发展为肺转移。单独使用依氟鸟氨酸以及与 drozitumab 联合治疗可减少肿瘤负担，并可防止骨肉瘤引起的骨破坏，同时减少肺转移的生长。这些结果表明，依氟鸟氨酸可能是一种有吸引力的治疗剂，单独使用或与 drozitumab 或杜拉明联合使用对骨肉瘤具有很强的抗癌活性。
