ABSTRACT
PURPOSE: Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. METHODS AND MATERIALS: We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. RESULTS: Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced by either a single dose or fractionated irradiation regimens in in vivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. In contrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension in dogs. CONCLUSIONS: CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer.
Subject(s)
Amifostine/administration & dosage , Gels/administration & dosage , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/administration & dosage , Radiodermatitis/prevention & control , Stomatitis/prevention & control , Amifostine/adverse effects , Animals , Blood Pressure/drug effects , Breast Neoplasms/radiotherapy , DNA Damage , Disease Models, Animal , Dogs , Drug Carriers , Female , Head and Neck Neoplasms/radiotherapy , Hypotension, Orthostatic/chemically induced , Mice , Mice, Inbred C57BL , Radiation Injuries, Experimental/drug therapy , Radiation-Protective Agents/adverse effects , Radiodermatitis/drug therapy , Random Allocation , Skin Neoplasms/radiotherapy , Stomatitis/drug therapy , Stomatitis/etiologyABSTRACT
BACKGROUND: Rabbit antithymocyte globulin (rATG) is a polyclonal mixture of immunoglobulin (Ig) G. It is used to prevent graft rejection and also graft versus host disease after transplantation. Its effect on lymphocyte function has been widely studied. Dendritic cells are central actors of the immune system. As antigen presenting cells, they are able to initiate, stimulate, and modulate immune responses. METHODS: In this study, we investigated rATG effects on in vitro differentiation and maturation of monocyte-derived dendritic cells (Mo-DCs). RESULTS: rATG inhibited maturation of immature Mo-DCs and allowed the generation of dendritic cells expressing ILT-3, CD123, CCR6 but not CCR7 and producing Indoleamine 2,3-dioxygenase mRNA as well as interferon-alpha. CONCLUSION: rATG polarizes in vitro Mo-DCs towards tolerogenic dendritic cells.
