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Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells
M. Hofer, M. Falk, D. Komůrková, I. Falková, A. Bačíková, B. Klejdus, E. Pagáčová, L. Štefančíková, L. Weiterová, KJ. Angelis, S. Kozubek, L. Dušek, Š. Galbavý,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV16-29835A
MZ0
CEP Register
- MeSH
- Alkaline Phosphatase genetics metabolism MeSH
- Amifostine pharmacokinetics pharmacology MeSH
- DNA Breaks, Double-Stranded drug effects MeSH
- Fibroblasts drug effects radiation effects MeSH
- Microscopy, Fluorescence methods MeSH
- Histones genetics metabolism MeSH
- Intracellular Signaling Peptides and Proteins genetics metabolism MeSH
- Comet Assay MeSH
- Humans MeSH
- Mercaptoethylamines pharmacokinetics MeSH
- MCF-7 Cells drug effects radiation effects MeSH
- DNA Repair drug effects MeSH
- DNA Damage drug effects MeSH
- Radiation-Protective Agents pharmacology MeSH
- Gamma Rays MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography-mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.
References provided by Crossref.org
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