title: Dexrazoxane mitigates epirubicin-induced genotoxicity in mice bone marrow cells.
abstract: Dexrazoxane is the only clinically approved cardioprotectant against anthracyclines-induced cardiotoxicity. Thus, detailed evaluation of the genotoxic potential of dexrazoxane and anthracyclines combination is essential to provide more insights into genotoxic and anti-genotoxic alterations that may play a role in the development of the secondary malignancies after treatment with anthracyclines. Thus, our aim was to determine whether non-genotoxic doses of dexrazoxane in combination with the anthracycline, epirubicin can modulate epirubicin-induced genotoxicity and apoptosis in somatic cells. Bone marrow micronucleus test complemented with fluorescence in situ hybridization assay and comet assay were performed to assess the genotoxicity of dexrazoxane and/or epirubicin. Apoptosis was analysed by using the annexin V assay and the occurrence of the hypodiploid DNA content. Generation of reactive oxygen species was also assessed in bone marrow by using the oxidant-sensing fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate. Dexrazoxane was neither genotoxic nor apoptogenic in mice at a single dose of 75 or 150mg/kg. Moreover, it has been shown that dexrazoxane affords significant protection against epirubicin-induced genotoxicity and apoptosis in the bone marrow cells in a dose-dependent manner. Epirubicin induced marked generation of intracellular reactive oxygen species and prior administration of dexrazoxane ahead of epirubicin challenge ameliorated accumulation of these free radicals. It is thus concluded that dexrazoxane can be safely combined with epirubicin and that pre-treatment with dexrazoxane attenuates epirubicin-induced generation of reactive oxygen species and subsequent genotoxicity and apoptosis. Thus, epirubicin-induced genotoxicity can be effectively mitigated by using dexrazoxane.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia, Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt, attiasm@yahoo.com.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Sheikh F
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Zoology Department, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia, Al-Jeraisy Chair for DNA Research, Zoology Department, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Quaiser
authors.initials: Q
authors.lastname: Saquib
authors.affiliation: Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia Department of Biochemistry, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Gamaleldin I
authors.initials: GI
authors.lastname: Harisa
authors.affiliation: Zoology Department, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia, Al-Jeraisy Chair for DNA Research, Zoology Department, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Abdulaziz A
authors.initials: AA
authors.lastname: Al-Khedhairy
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity; D002316:Cardiotonic Agents / Q000494:pharmacology*; D020552:Comet Assay; D053960:DNA Breaks / Q000187:drug effects; D064730:Dexrazoxane / Q000494:pharmacology*; D015251:Epirubicin / Q000633:toxicity*; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D064730:Dexrazoxane; D015251:Epirubicin