Abstract
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.
Highlights
Osteosarcoma (OS) is the most common primary type of cancer that develops in the bone and accounts for 20% of all primary osseous neoplasms [1, 2]
This study investigates the cytotoxic activity of evofosfamide alone and in combination with dulanermin and drozitumab against human OS cells in vitro and in vivo, using a clinically relevant orthotopic mouse model of OS and on their subsequent lung metastases
Evofosfamide cooperates with drozitumab and dulanermin, displaying increased hypoxia-selective cytotoxicity against OS cells
Summary
Osteosarcoma (OS) is the most common primary type of cancer that develops in the bone and accounts for 20% of all primary osseous neoplasms [1, 2]. Most OS occur in young adults and children and usually develop in areas where the bone is rapidly growing such as the proximal tibia, distal femur, and proximal humerus [3]. The type, combination as well as the doses of chemotherapeutic agents given as well as the sensitivity of the tumor cells determine the patients’ response to treatment. Despite these advances in treatment, drug resistance still remains a problem [6]. Conventional chemotherapeutic drugs have a significant impact on normal bone health, leading to a greater risk of developing osteoporosis and myelosuppression due to toxicities in the bone marrow [7, 8]
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