title: A high-throughput screen for alpha particle radiation protectants.
abstract: 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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Seideman
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000512:Alpha Particles / Q000009:adverse effects*; D017607:Aluminum Compounds / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D018922:HL-60 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D009566:Nitrates / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D017607:Aluminum Compounds; D009566:Nitrates; D011837:Radiation-Protective Agents; D054852:Small Molecule Libraries; C050609:aluminum nitrate