The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice.
Bone marrow suppression due to exposure to ionizing radiation is a significant clinical problem associated with radiation therapy as well as with nonmedical radiation exposure. Currently, there are no small molecule agents available that can enhance hematopoietic regeneration after radiation exposure. Here, we report on the effective mitigation of acute hematopoietic radiation syndrome in mice by the synthetic triterpenoid, RTA 408. The administration of a brief course of RTA 408 treatment, beginning 24 h after lethal doses of radiation to bone marrow, significantly increased overall survival. Importantly, treatment with RTA 408 led to the full recovery of steady state hematopoiesis with normalization of the frequency of hematopoietic stem and progenitor cells. Moreover, hematopoietic stem cells from RTA 408-mitigated mice showed lineage-balanced, long-term, multilineage potential in serial transplantation assays, indicative of their normal self-renewal activity. The potency of RTA 408 in mitigating radiation-induced bone marrow suppression makes it an attractive candidate for potential clinical use in treating both therapy-related and unanticipated radiation exposure.
a Department of Pediatrics, Oregon Stem Cell Center, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239.
Devorah C
DC
Goldman
Vitali
V
Alexeev
Elizabeth
E
Lash
Chandan
C
Guha
Ulrich
U
Rodeck
William H
WH
Fleming
D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D011839:Radiation, Ionizing; D011878:Radiotherapy / Q000009:adverse effects; D014315:Triterpenes / Q000008:administration & dosage*; D014916:Whole-Body Irradiation
D014315:Triterpenes; C000589490:omaveloxolone