| Autor: |
Zaher A; Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA., Mapuskar KA; Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA., Petronek MS; Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA., Tanas MR; Department of Pathology, The University of Iowa, Iowa City, IA 52242, USA., Isaacson AL; Department of Pathology, The University of Iowa, Iowa City, IA 52242, USA.; Department of Pathology, The Cleveland Clinic, Cleveland, OH 44195, USA., Dodd RD; Department of Internal Medicine, Division of Hematology and Oncology, The University of Iowa, Iowa City, IA 52242, USA., Milhem M; Department of Internal Medicine, Division of Hematology and Oncology, The University of Iowa, Iowa City, IA 52242, USA., Furqan M; Department of Internal Medicine, Division of Hematology and Oncology, The University of Iowa, Iowa City, IA 52242, USA., Spitz DR; Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA., Miller BJ; Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, IA 52242, USA., Beardsley RA; Galera Therapeutics Inc., 2 West Liberty Blvd., Suite 110, Malvern, PA 19355, USA., Allen BG; Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA. |
| Abstrakt: |
Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs. |
