title: Erythrocytotoxicity of tiazofurin in vivo and in vitro detected by scanning probe microscopy.
abstract: Tiazofurin (TZF) is a cytostatic drug that leads to depletion of the GTP pool in tumor and normal cells via its active metabolite tiazofurin-adenine dinucleotide (TAD). TAD was detected in different cell lines, but not in erythrocytes, so the mechanism of erythrocytotoxicity of TZF remains unclear. The purpose of this study was to evaluate in vitro and in vivo action of tiazofurin on rat erythrocytes (RBC). After two decades of clinical trials the question of erythrocytotoxicity of TZF had remained unexplained making this study justified. Since we have previously demonstrated early erythrocytotoxic effects in male Wistar rats, we extend this finding on isolated RBC. Isolated erythrocytes from untreated animals were treated in buffered solution or plasma containing TZF. In addition, groups of 10 rats were treated with 200 and 1000 mg/kg of TZF and hematologic parameters were analyzed by flowcytometry and by the analysis of the peripheral blood smears. Early signs of hemolysis or aberrant structures were monitored by scanning probe microscopy (SPM). We suggest that correlation exists between early erythrocytotoxicity and irregularities in erythrocyte morphology and membrane integrity. We also found that TZF affects responsiveness to oxidative stress. This is in concordance with flowcytometric findings describing anisocytosis and anisochromosis of RBC.
authors.affiliation: Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, Serbia and Montenegro Belgrade 11001.
authors.forename: Vesna
authors.initials: V
authors.lastname: Vranić-Mandusić
authors.forename: Vesna
authors.initials: V
authors.lastname: Subota
authors.forename: Kiril
authors.initials: K
authors.lastname: Savovski
authors.forename: Ljubica
authors.initials: L
authors.lastname: Medić
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dramićanin
authors.forename: Olga
authors.initials: O
authors.lastname: Jozanov-Stankov
authors.forename: Dusan
authors.initials: D
authors.lastname: Popov-Celeketić
authors.forename: Milan
authors.initials: M
authors.lastname: Jokanović
authors.forename: Bogomir
authors.initials: B
authors.lastname: Dimitrijević
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002374:Catalase / Q000097:blood; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000097:blood; D008297:Male; D020527:Microscopy, Scanning Probe; D051381:Rats; D012156:Reticulocytes / Q000378:metabolism; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000633:toxicity*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D017392:Thiobarbituric Acid Reactive Substances; D012254:Ribavirin; D002374:Catalase; D005979:Glutathione Peroxidase; C033706:tiazofurin