RRx-001 Radioprotection: Enhancement of Survival and Hematopoietic Recovery in Gamma-Irradiated Mice.

Kimberly J Jurgensen,Nacer D Abrouk,Bryan Oronsky,Reid D Landes,Lynnette H Cary,William K J Skinner,Andrew E Graff,Thomas A Summers,William E Culp

doi:10.3389/fphar.2021.676396

Abstract

The present studies evaluate the in vivo prophylactic radioprotective effects of 1-bromoacetyl-3, 3-dinitroazetidine (RRx-001), a phase III anticancer agent that inhibits c-myc and downregulates CD-47, after total body irradiation (TBI), in lethally and sublethally irradiated CD2F1 male mice. A single dose of RRx-001 was administered by intraperitoneal (IP) injection 24 h prior to a lethal or sublethal radiation dose. When irradiated with 9.35 Gy, the dose lethal to 70% of untreated mice at 30 days (LD70/30), only 33% of mice receiving RRx-001 (10 mg/kg) 24 h prior to total body irradiation (TBI) died by day 30, compared to 67% in vehicle-treated mice. The same pretreatment dose of RRx-001 resulted in a significant dose reduction factor of 1.07. In sublethally TBI mice, bone marrow cellularity was increased at day 14 in the RRx-001-treated mice compared to irradiated vehicle-treated animals. In addition, significantly higher numbers of lymphocytes, platelets, percent hematocrit and percent reticulocytes were observed on days 7 and/or 14 in RRx-001-treated mice. These experiments provide proof of principle that systemic administration of RRx-001 prior to TBI significantly improves overall survival and bone marrow regeneration.

Highlights

Ionizing radiation causes damage to normal tissues, ranging from genetic mutations to cell death (Hall and Giaccia, 2012)
The irradiated vehicle-treated group (4C) showed a significant loss of bone marrow cellularity with an increase in infiltration by adipocytes compared to the irradiated RRx-001treated group (4D) on day 14 where significant recovery of bone marrow cellularity was observed. This is the first study to report that RRx-001 administered IP 24 h prior to an LD70/30 dose of total body irradiation (TBI) significantly decreased and delayed lethality in CD2F1 mice
33% of mice receiving vehicle before undergoing irradiation with the LD70/30 dose survived to 30 days, compared to 67% of the mice pretreated dropped below 90% during the duration of the study and maintained a grade of 5 (Figure 3A)

Summary

Introduction

Ionizing radiation causes damage to normal tissues, ranging from genetic mutations to cell death (Hall and Giaccia, 2012). The harmful effects of ionizing radiation on normal tissues are a major concern for military and emergency responders to nuclear accidents and terrorist events due to the risk of acute and delayed radiation injuries (CDC, 2010). Despite significant technological improvements in radiation delivery in recent years, normal tissue toxicity remains a major dose-limiting factor in therapeutic radiology (Johnke et al, 2014; Nakamura et al, 2014). Extensive efforts over the past several decades have resulted in two Food and Drug Administration (FDA) approved drugs available for prophylactic radioprotection of nonhematopoietic tissue, amifostine (Ethyol) and palifermin (Kepivance) (Wasserman and Brizel, 2001). Neither amifostine nor palifermin have been FDA approved for accidental or emergency radiation exposures

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