Avasopasem Manganese acts as both a Radioprotector and a Radiomitigator of Radiation-Induced Acute or Late Effects.

Abstract

The pentaazamacrocyclic superoxide dismutase mimetic, Avasopasem Manganese (AVA), has been shown in clinical trials to reduce the severity and duration of acute oral mucositis (OM) and acute esophagitis in patients treated for head and neck and lung cancers, respectively, by radiotherapy using conventional fractionation protocols. Here, the radioprotective effects of AVA were tested in normal tissues after high dose per fraction radiation exposures to determine whether: radioprotective effects of AVA were still present after doses like those used with stereotactic ablative radiotherapy (SAbR); AVA protected against late normal tissue responses; and, whether AVA could act as a radiomitigator of adverse normal tissue events. With AVA, residual DNA lesions and micronuclei were reduced in HBEC3 KT but increased in H1299 cells 24h post-irradiation. Furthermore, radiation-induced mutations and chromosome aberrations were reduced in WTK-1 lymphoblast cells. The radioprotective effects of AVA at high dose per fraction were then tested against both acute and late normal tissue effects. When provided prior to radiation, AVA reduced the extent of epithelial cell layer degradation of mouse tongue irradiated with a single dose of 17 Gy and reduced radiation recall when a second dose of radiation of 12 or 17 Gy was given two weeks following the initial 17 Gy dose. In addition, when provided after radiation, there was a modest but significant reduction in adverse epithelial layer response. Radiation-induced lung fibrosis, determined at 24 weeks post-irradiation, was also reduced when AVA was delivered 1 hour prior to irradiation after a single dose of 54 Gy. When AVA was provided 24h after 54 Gy and given daily (Monday-Friday) for increasing numbers of weeks, fibrosis was progressively reduced as the length of AVA treatment increased. However, AVAs effect on fibrosis decreased as the time between irradiation and post-irradiation AVA application increased. These studies confirm the efficacy of AVA as a radioprotector and mitigator of both radiation-induced acute and late effects after high dose per fraction exposures while not protecting tumor cells to radiation exposure.