| A high-throughput screen for alpha particle radiation protectants. | |
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MedLine Citation:
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PMID: 20658946 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Alpha-particle-emitting elements are of increasing importance as environmental and occupational carcinogens, toxic components of radiation dispersal devices and accidents, and potent therapeutics in oncology. Alpha particle radiation differs from radiations of lower linear energy transfer in that it predominantly damages DNA via direct action. Because of this, radical scavengers effective for other radiations have had only limited effect in mitigating alpha particle toxicity. We describe here a simple assay and a pilot screen of 3,119 compounds in a high-throughput screen (HTS), using the alpha-particle-emitting isotope, ²²⁵Ac, for the discovery of compounds that might protect mammalian cells from alpha particles through novel mechanisms. The assay, which monitored the viability of a myeloid leukemic cell line upon alpha particle exposure, was robust and reproducible, yielding a Z' factor of 0.66 and a signal-to-noise ratio of nearly 10 to 1. Surprisingly, 1 compound emerged from this screen, epoxy-4,5-α-dihydroxysantonin (EDHS), that showed considerable protective activity. While the value of EDHS remains to be determined, its discovery is a proof of concept and validation of the utility of this HTS methodology. Further application of the described assay could yield compounds useful in minimizing the toxicity and carcinogenesis associated with alpha particle exposure. |
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Authors:
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Jonathan H Seideman; David Shum; Hakim Djaballah; David A Scheinberg |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-07-26 |
Journal Detail:
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Title: Assay and drug development technologies Volume: 8 ISSN: 1557-8127 ISO Abbreviation: Assay Drug Dev Technol Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-26 Completed Date: 2011-04-18 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 101151468 Medline TA: Assay Drug Dev Technol Country: United States |
Other Details:
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Languages: eng Pagination: 602-14 Citation Subset: IM |
Affiliation:
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Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alpha Particles
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adverse effects* Aluminum Compounds / metabolism Cell Line, Tumor DNA Damage Drug Evaluation, Preclinical / methods* HL-60 Cells High-Throughput Screening Assays* Humans Nitrates / metabolism Radiation-Protective Agents / pharmacology* Reproducibility of Results Small Molecule Libraries |
| Grant Support | |
ID/Acronym/Agency:
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5 P30 CA008748-44/CA/NCI NIH HHS; CA 33049/CA/NCI NIH HHS; CA 55349/CA/NCI NIH HHS; R01 CA055349-18/CA/NCI NIH HHS; R01 CA055349-19/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aluminum Compounds; 0/Nitrates; 0/Radiation-Protective Agents; 0/Small Molecule Libraries; 13473-90-0/aluminum nitrate |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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