title: Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells.
abstract: The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposide-induced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, Saudi Arabia.
authors.forename: S A
authors.initials: SA
authors.lastname: Bakheet
authors.forename: S M
authors.initials: SM
authors.lastname: Attia
authors.forename: N M
authors.initials: NM
authors.lastname: Al-Rasheed
authors.forename: M M
authors.initials: MM
authors.lastname: Al-Harbi
authors.forename: A E
authors.initials: AE
authors.lastname: Ashour
authors.forename: H M
authors.initials: HM
authors.lastname: Korashy
authors.forename: A R
authors.initials: AR
authors.lastname: Abd-Allah
authors.forename: Q
authors.initials: Q
authors.lastname: Saquib
authors.forename: A A
authors.initials: AA
authors.lastname: Al-Khedhairy
authors.forename: J
authors.initials: J
authors.lastname: Musarrat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D033481:Chromosomes, Mammalian / Q000378:metabolism; D053960:DNA Breaks / Q000187:drug effects; D004249:DNA Damage; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D011929:Razoxane / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013713:Teniposide / Q000633:toxicity*
chemical_list: D017382:Reactive Oxygen Species; D011929:Razoxane; D013713:Teniposide; D053148:Caspase 3; D005978:Glutathione