Yeast DEL Assay Detects Protection against Radiation-Induced Cytotoxicity and Genotoxicity: Adaptation of a Microtiter Plate Version

Hafer, Kurt; Rivina, Yelena; Schiestl, Robert H.

doi:10.1667/rr2059.1

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…When the strain is exposed to mutagens, carcinogens or clastogens, a high number of breaks are created which, in an attempt to repair the break by recombination, results in the deletion of the intervening sequence and the re‐creation of a functional HIS3 gene allowing the yeast to grow on histine‐deficient media [Brennan and Schiestl, ]. This assay has been adapted for high‐throughput screening and has also been used to perform chemical screens for differential sensitivity to radiation [Hafer et al, ]. Thus, this screen has the ability to identify chemicals that interfere with conserved DNA repair pathways.…”

Section: Introductionmentioning

confidence: 99%

Models of germ cell development and their application for toxicity studies

Ferreira

Allard

2015

Environ and Mol Mutagen

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Germ cells are unique in their ability to transfer genetic information and traits from generation to generation. As such, the proper development of germ cells and the integrity of their genome are paramount to the health of organisms and the survival of species. Germ cells are also exquisitely sensitive to environmental influences although the testing of germ cell toxicity, especially in females, has proven particularly challenging. In this review, we first describe the remarkable odyssey of germ cells in mammals, with an emphasis on the female germline, from their initial specification during embryogenesis to the generation of mature gametes in adults. We also describe the current methods used in germ cell toxicity testing and their limitations in examining the complex features of mammalian germ cell development. To bypass these challenges, we propose the use of alternative model systems such as Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and in vitro germ cell methods that have distinct advantages over traditional toxicity models. We discuss the benefits and limitations of each approach, their application to germ cell toxicity studies, and the need for computational approaches to maximize the usefulness of these models. Together, the inclusion of these alternative germ cell toxicity models will be invaluable for the examination of stages not easily accessible in mammals as well as the large scale, high-throughput investigation of germ cell toxicity.

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Section: Introductionmentioning

confidence: 99%

Models of germ cell development and their application for toxicity studies

Ferreira

Allard

2015

Environ and Mol Mutagen

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“…One of the compounds in Figure 5 , 5346057 (a.k.a. 057, BCN057, or YEL002), was of interest because it was identified as active in another HTS yeast screen, performed in parallel based on the DEL assay that measures mitigation of radiation cytotoxicity and genotoxity in the diploid yeast S. cerevisiae strain RS112 ( Hafer et al, 2010 ; Kim et al, 2011 ) indicating that a conserved pathway is involved in mitigation. 057 had a dose modification factor for H-ARS of 1.15 when given s. c. in a daily 5 day course starting 24 h after WBI (Drs.…”

Section: Resultsmentioning

confidence: 99%

Classes of Drugs that Mitigate Radiation Syndromes

et al. 2021

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We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 “hits.” Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

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“…Reversion to his+ can be measured by plating (37), or more recently in microtiter plate format, using a colorimetric readout (38,39). This assay has thus far proven to be very accurate, discriminating between carcinogens and noncarcinogens of the same chemical class, and showing a 92% correlation with two prokaryotic genotoxicity assays (Ames and UmuC) (39).…”

Section: Yeast Del Assaymentioning

confidence: 99%