title: Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and 5-fluorouracil but Interacts with Doxorubicin Leading to Side Changes in Redox Equilibrium.
abstract: Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules.
authors.affiliation: Department of Pneumology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Mandziuk
authors.affiliation: Department of Histology and Embryology, Medical University of Lublin, Lublin, Poland.
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Matysiak
authors.affiliation: Independent Medical Biology Unit, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Korga
authors.affiliation: Department of Anatomy, Medical University of Lublin, Lublin, Poland.|St. John Cancer Center, Lublin, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Burdan
authors.affiliation: Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Pasnik
authors.affiliation: Regional Dental Clinic Independent Public Health Care of Lublin, Lublin, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Hejna
authors.affiliation: Department of Paediatric Pulmonology and Rheumatology, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Korobowicz-Markiewicz
authors.affiliation: 1st Department of Radiology and Nuclear Medicine, Medical University of Lublin, Lublin, Poland.
authors.forename: Luiza
authors.initials: L
authors.lastname: Grzycka-Kowalczyk
authors.affiliation: 1st Department of Anaesthesiology and Intensive Care, Medical University of Lublin, Lublin, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Kowalczyk
authors.affiliation: Department of Applied Pharmacy, Medical University of Lublin, Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Poleszak
authors.affiliation: Department of Histology and Embryology, Medical University of Lublin, Lublin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jodlowska-Jedrych
authors.affiliation: Independent Medical Biology Unit, Medical University of Lublin, Lublin, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dudka
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D002784:Cholesterol / Q000097:blood; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; D014280:Triglycerides; D000077704:Tirapazamine; D004317:Doxorubicin; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D002945:Cisplatin; D005472:Fluorouracil