Abstract
Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.
Highlights
The threat level for exposure of large numbers of people to ionizing radiation has been significantly elevated following the worldwide rise in terrorism
85,000 small molecules from chemical libraries were added in an high throughput screen (HTS) format to pre-irradiated (2Gy) TIL1 lymphocytic cells that are sensitive to radiation apoptosis
All except #1 and #8 were tested in vivo. They were injected in 1% Cremophor s.c. into C3H male mice (8 per group) starting 24 hrs after 7.725Gy whole body irradiation (WBI) (LD70/30 estimate), daily for 5 days
Summary
The threat level for exposure of large numbers of people to ionizing radiation has been significantly elevated following the worldwide rise in terrorism. Since radiation-induced cell death and tissue damage are classically thought of as consequences of free radical generation, DNA damage repair, and rapid apoptosis; events that are largely over within hours of exposure, delayed treatment shifts the spotlight to downstream processes that interpret and amplify initial radiation-induced DNA damage responses Notwithstanding this stringent requirement, a number of compounds have been identified that mitigate lethality from acute radiation syndromes (ARS) in preclinical models [1,2,3,4,5,6,7,8,9,10]; structure-activity relationships and pathways to mitigation are generally obscure and agents active against the broad spectrum of possible radiation syndromes are lacking. These compounds have low toxicity, and some anti-tumor action, suggesting that they may be of use in the broader context of radiotherapy for cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
