title: Comparison of hypoxic cell radiosensitizers, KIN-804, KIN-844, KIN-806 and TX-1877, on brain and liver metabolizing capacities in mice bearing Ehrlich ascites carcinoma.
abstract: The biochemical effects of the 2-nitroimidazole hypoxic cell radiosensitizers KIN-804, KIN-806, and their analogues KIN-844 and TX-1877 on brain acetylcholinesterase (AChE) and hepatic free radical scavenging systems, such as reduced glutathione (GSH) and glucose-6-phosphate dehydrogenase (G-6-PDH) levels, and hepatic antioxidants, such as superoxide dismutase (SOD) and catalase, were evaluated in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The assay of brain AChE revealed nonsignificant changes with all drugs examined. To evaluate the hepatic metabolic capacity, groups of mice were divided into control, EAC-inoculated, 10-Gy local gamma-irradiated, and KIN-804, KIN-844, KIN-806, or TX-1877 (50 mg/kg body weight, i.p.) groups, and gamma-irradiation was combined with each drug. EAC inoculation markedly suppressed GSH, G-6-PDH, SOD, and catalase levels. On the other hand, treatment with gamma-irradiation significantly enhanced them. The treatment of EAC-bearing mice with each drug alone in the absence of gamma-irradiation revealed that KIN-806 and its derivative TX-1877 showed antitumor activity through their significant recovery of GSH and SOD levels, respectively, in the EAC-bearing mice group. Similarly, the combined treatment of EAC-bearing mice with gamma-irradiation with each of the drugs tested showed that KIN-806 and TX-1877 significantly increased GSH and SOD, and to a lesser extent G-6-PDH and catalase levels. On the other hand, KIN-804 and KIN-844 had only a nonsignificant effect on all parameters examined. In conclusion, these data reveal that the administration of KIN-806 and TX-1877 with or without subsequent gamma-irradiation, resulted in significant recovery of GSH and SOD activities that were inhibited by EAC inoculation.
authors.affiliation: Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt.
authors.forename: Farid Ahmed
authors.initials: FA
authors.lastname: Abou-Bedair
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Medhat
authors.initials: M
authors.lastname: Abu-Zeid
authors.forename: Seiichi
authors.initials: S
authors.lastname: Inayama
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects*; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: C115855:2-nitroimidazole acetamide; D016166:Free Radical Scavengers; D006877:Hydroxamic Acids; C121164:KIN 806; C400442:KIN 844; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C076264:2-nitroimidazole-1-methylacetohydroxamate; D005954:Glucosephosphate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase; D000110:Acetylcholinesterase; D005978:Glutathione