[Effect of azole derivatives on lucigenin-dependent microsome chemiluminescence]. / Vliianie proizvodnykh azolov na liutsigenin-zavisimuiu khemiliuminestsentsiiu mikrosom.

Both metronidazole and aminotriazole increased while sanazole (drug AK-2123) decreased the NADPH/lucigenin-dependent chemiluminescence of liver microsomes of phenobarbital-treated rats. Sanazole strongly inhibited the lucigenin-dependent chemiluminescence in the enzyme system of xanthine-xanthine oxidase. Aminotriazole and metronidazole were less potent inhibitors of chemiluminescence less than sanazole. All these azole derivatives did not absorb light in the region of light emission of lucigenin. Both lucigenin and sanazole increased the rate of cytochrome c reduction by microsomes in case of using NADPH as a donor of electrons, whereas no effect of metronidazole and aminotriazole on this rate was found. The sanazole inhibition of lucigenin-dependent chemiluminescence could reflect competition between sanazole and lucigenin for electrons in the active centre of flavin reductases. Thus, microsomal NAD(P)H-reductases can be potentially involved in a bioactivation of sanazole. Lucigenin-dependent chemiluminescence cannot be used for measuring the modulating action of agents on reactive oxygen species production in the microsomes, but it may be used for luminometrical studies of enzyme complex NAD(P)H-reductases/cytochrome P450 in model systems.

[Effect of sanazole and metrinidazole on production of reactive oxygen species by macrophages]. / Vliianie sanazola i metronidazola na produktsiiu aktivnykh form kisloroda makrofagami.

The in vitro effect of sanazole (AK-2123; N-(2'-methoxyethyl)-2-[3"-nitro-1"-triazolyl]acetamide) and metronidazole (1-beta-hydroxyethyl-2-methyl-5-nitroimidazole) on phorbol-12-myristate-13-acetate (PMA)-stimulated and spontaneous (without stimulation by PMA) production of reactive oxygen species (ROS) by peritoneal and splenic murine macrophages was studied. ROS production was analyzed using fluorescent probe 2',7'-dichlorofluoresceine diacetate (DCFH-DA). An increase in the spontaneous production of ROS by macrophagal cells with therapeutic concentration of sanazole (0.6-1.25 mM) in the incubation medium was observed. At these concentrations metronidazole had no effect on spontaneous production of ROS by macrophagal cells. PMA-stimulated ROS production was inhibited by high concentrations (2.5-10 mM) of sanazole and metronidazole. The spontaneous generation of ROS by peritoneal macrophages was stimulated by sanazole at all tested concentrations (0.6-10 mM).

[Effect of platinum derivatives on microsomal NADPH-oxidoreductase activity]. / Vliianie proizvodnykh platiny na aktivnost' mikrosomnykh NADPH-oksidoreduktaz.

The influence of platinum derivatives, cisplatin (cis-diamminedichloroplatinum) and imidazolplatin (cis-diimidazoledichloroplatinum) on the activity of rat liver microsomal NADPH-oxidoreductases was investigated in vitro using spectrophotometrical and chemiluminometrical methods. In the range of concentrations from 1 to 12 microM cisplatin inhibited NADPH-cytochrome c-reductase activity and NADPH/lucigenin-dependent chemiluminescence of microsomes. The 3 microM cisplatin decreased the NADPH-dependent reductase activity by 50%. At concentrations less than 2.5 mM sanazole (drug AK-2123) did not prevent the inhibiting influence of cisplatin on microsomal NADPH-dependent reductases. Imidazolplatin insignificantly inhibited NADPH-reductases. It is concluded that negligible inhibiting effect of imidazolplatin on microsomal NADPH-oxidoreductase allows us to consider this platinum derivative as a promising compound for further experimental trials as anticancer drug with low toxic action on the normal tissues of an organism.

[The radiosensitizer AK-2123 enhances sensitivity of MDR-tumors to Mitomycin C]. / Povyshenie chuvstvitel'nosti lekarstvenno-ustoichivykh opukholei k mitomitsinu C s pomoshch'iu radiosensibilizatora AK-2123.

It was demonstrated that radiosensitizer AK-2123 of the triazole group significantly enhanced the sensitivity of MDR-strains of P388 murine leukemia (reported by the authors earlier) to mitomycin C (MMC). There was a direct correlation between the modulating effect of AK-2123 and dose increase from 1 to 10 mg/kg. The effect depended on the initial sensitivity of the MMC-resistant strain which in turn correlated with the absence or presence of sorcin (cytosole low-molecular Ca(2+)-binding protein) gene coamplification in the mdr-amplicon. Since AK-2123 was reported earlier by us to disrupt active Ca(2+)-transport, it is suggested that the modulating effect of the radiosensitizer was at least partially due to said disruption. AK-2123 exerted no antitumor action of its own whatsoever. It could neither modify the sensitivity of parent strain P388 to MMC, nor overcome the cross resistance of one of the MDR-tumor strains under study to such drugs as etoposide and adriablastin.