共查询到20条相似文献,搜索用时 46 毫秒
1.
D N Rao L Harman A Motten J Schreiber R P Mason 《Archives of biochemistry and biophysics》1987,255(2):419-427
Nitrofurantoin, misonidazole, and metronidazole were reduced to their corresponding nitro anion radicals by ascorbate in anaerobic solutions at high pH. The nitrofurantoin anion radical could be detected at neutral pH. In neutral solutions, the nitro anion radicals of misonidazole and metronidazole were too unstable to be observed by electron spin resonance spectroscopy. At neutral pH, solutions containing ascorbate, nitrofurantoin, or misonidazole consumed oxygen. The addition of superoxide dismutase, catalase, or both superoxide dismutase and catalase decreased the rate of oxygen consumption. These results show that nitro anion radicals are formed by reduction with ascorbate, and superoxide anion radical and hydrogen peroxide are produced by reactions of these radicals with oxygen. 相似文献
2.
D E Moore 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1985,47(5):563-568
The free-radical reactivity of the nitroimidazole derivatives metronidazole, misonidazole, benznidazole and ornidazole was investigated by observing their effect on the polymerization of acrylamide in aqueous solution. Free-radical polymerization was initiated by the thermal decomposition of potassium peroxydisulphate at 50 degrees C. Measurement of the polymerization rate showed an inhibitory effect of the nitroimidazoles which was greatly enhanced when the system was irradiated with u.v. light near their absorption maximum of 320-325 nm. Analysis of the competitive kinetics of the system enabled calculation of the rate constant for reaction of the ground state and photoexcited nitroimidazole with the polyacrylamide free radicals. No significant difference between the various nitroimidazoles could be found in the dark reaction, but in the u.v.-irradiated system the order of reactivity (misonidazole greater than benznidazole greater than metronidazole approximately equal to ornidazole) was the same as the reported relative mutagenic, cytotoxic and radiosensitizing potency of the compounds. These results imply that the excited states of the nitroimidazoles are important to their activity in radical-radical reactions. 相似文献
3.
The spectrophotometric method was used to study the rate of chemical reduction of misonidazole and metronidazole by NH4Cl and Zn in the atmosphere of argon and oxygen. Reduction of drugs increased their toxicity for hypoxic and oxygenated E. coli B/r. The reduced metronidazole is a more effective radiosensitizer of hypoxic E. coli B/r than the original compound. 相似文献
4.
P J Deschavanne D Debieu N Chavaudra E P Malaise 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1985,48(2):213-221
The cytotoxic and radiosensitizing effects of misonidazole have been studied on glutathione synthetase deficient fibroblasts and on their controls. At any concentration from 0.1 to 4 mM, deficient cells are more sensitive to the cytotoxic effect of misonidazole than the control cells. The differential effect between the two cell strain concerns both the shoulder and the slope of the survival curve, thus suggesting that NPSH play a role in the determination of misonidazole cytotoxicity. Like oxygen, misonidazole clearly sensitizes deficient cells to a lesser extent than control cells. For both cell strains, the maximum sensitizing effect of misonidazole is very close to that of oxygen (1.5 and 1.5 for deficient cells, 2.8 and 2.9 for control cells, respectively). The sensitizing effect of misonidazole appears in the same concentration range for both cell strains, with a maximal effect at lower concentrations for deficient cells. 相似文献
5.
Complexes of general formula [PtCl2(NH3)L] with one radiosensitizing ligand per platinum are compared with ligand L alone, complexes with two radiosensitizers per platinum [PtCl2L2], and their analogs with NH3 ligands, with respect to radiosensitizing properties and toxicity in CHO cells. Radiosensitizing ligands, L, were misonidazole, metronidazole, 4(5)-nitroimidazole, and 2-amino-5-nitrothiazole, and the ammine analogs were cis- and trans-DDP [diamminedichloroplatinum(II)] and the monoammine, K[PtCl3(NH3)]. Results are related to a previous study on plasmid DNA binding by these series. The toxicity of the mono series [PtCl2(NH3)L], attributable to DNA binding, is much higher than the corresponding bis complexes, [PtCl2L2]. For L = misonidazole, toxicity is similar to the monoammine, but higher in hypoxic than in aerobic cells. trans-[PtCl2(NH3)-(misonidazole)] is more toxic than the cis isomer. Except for L = 4(5)-nitroimidazole, the complexes [PtCl2(NH3)L] are more toxic than L in air and hypoxia. Hypoxic radiosensitization by the mono complexes is comparable to the monoammine and is not better than free sensitizers, again except for L = 4(5)-nitroimidazole. Significantly lower sensitization is observed in oxic cells. The bis complexes [PtCl2L2], which do not bind to DNA as well as the mono complexes, are less effective radiosensitizers and less toxic than the [PtCl2(NH3)L] series. 相似文献
6.
D E Moore 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1987,51(1):45-51
Laser flash photolysis at 355 nm of misonidazole or metronidazole in aqueous solutions produced the relatively long-lived nitro radical anion as the only observable transient species. When 266 nm excitation was used, a small yield of solvated electron was observed. It is suggested that the nitroimidazole first undergoes photoionization and the photoelectrons are scavenged by ground state nitroimidazole molecules to produce the nitro radical anion. Alternatively, added EDTA or carbonate ion acted as an electron donor to the excited state nitroimidazole molecule, thereby increasing the yield of nitro radical anion. The transient yield from metronidazole was about half that from misonidazole, while the phosphorescence intensity of metronidazole in an ethanol glass was about 20 times that of misonidazole. The misonidazole n, pi* triplet state is more easily reduced than that of metronidazole and, in the presence of an electron donor, the radical anion is postulated to result from electron transfer to the triplet state of the nitroimidazole. 相似文献
7.
K R Austen T J Jenner P O'Neill E M Fielden 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1987,52(2):281-288
Using a cellular fast-mixing technique, the time course of radiation sensitization of hypoxic, V79 cells by various concentrations of RSU-1069 (0.25-2.5 mmol dm-3) and misonidazole (2.5-50 mmol dm-3) have been studied to distinguish between fast chemical processes and the much slower biochemical responses to ionizing radiation and the monofunctional alkylating action of RSU-1069. Under conditions of equi-concentration, misonidazole and RSU-1069 show similar radiosensitizing efficiencies for pre-irradiation contact times up to 1 s. The values of the sensitizer enhancement ratio of approximately 1.5 for both 2-nitroimidazoles (2.5 mmol dm-3) is considerably less than that of 1.9-2.8 determined with misonidazole for a pre-irradiation contact time of 1 h under hypoxia. It is proposed that the enhanced radiosensitizing efficiency of RSU-1069 compared to that of misonidazole after long contact times involves, in part, the formation of 'sub-toxic' damage probably involving monofunctional and/or bifunctional action of RSU-1069 prior to irradiation. 相似文献
8.
D L Leonidze G G Afanas'ev K P Khanson L P Vartanian A M Poverenny? 《Radiobiologiia》1986,26(2):231-235
In experiments on mice with solid sarcoma 37, a study was made of modification of the radiosensitizing effect of metronidazole. The increase in the leucotic interferon titre, induced by the interferon synthesis inductors, did not influence the radiosensitizing efficiency of metronidazole: after the administration of the repair inhibitor, 8-bromocaffeine, the coefficient of suppression of tumor growth was higher and the number of mice with the regressed tumors greater as compared to animals affected by metronidazole and radiation. 相似文献
9.
Pretreatment of V79- WNRE cells with 150 microM diethylmaleate for 1 hr at 37 degrees C caused a decrease in intracellular glutathione levels to approximately 10-15% of control levels (0.5 vs 5.0 nmol/10(6) cells). The cells could be washed free of diethylmaleate and held at 0 degree C for several hours without toxicity and with no increase in glutathione concentration, although the glutathione concentration rapidly increased to normal levels at higher temperatures. Survival curves were determined as a function of oxygen or misonidazole concentration (the latter in the absence of oxygen). A new "thin-film" technique was used to avoid changes in oxygen concentration because of radiochemical or cellular oxygen consumption. Glutathione depletion itself caused a small but consistent radiosensitization of hypoxic cells (dose enhancement ratio of 1.2). However, glutathione depletion caused a profound change in the radiosensitizing efficiency of misonidazole, with a decrease in Km of about sevenfold from 0.6 to 0.09 mM. In contrast, only a 2.5-fold decrease was found in the Km for radiosensitization by oxygen with diethylmaleate pretreatment. These results suggest a fundamental problem with the conventional theory of radiosensitivity whereby one considers a first-order competition for reaction with target radicals between radical-fixing versus radical-repairing species. It also suggests difficulties in the interpretation of glutathione as the only endogenous protective species. 相似文献
10.
A study was made of the effect of metronidazole and isometronidazole on the survival rate of irradiated and nonirradiated E. coli B/r cells. These substances had similar radiosensitizing activity with regard to anoxic cells and did not sensitize cells irradiated in the air. At the same time, isometronidazole was found to be less toxic than metronidazole. 相似文献
11.
A study was made of Ehrlich ascites tumor growth and life span of mice bearing hemoblastosis La after inoculation of tumor cells subjected, in anaerobic conditions, to the effect of gamma-radiation and/or metronidazole and isometronidazole. It was shown that the cytotoxic effect of isometronidazole was less manifest than that of metronidazole the radiosensitizing effect, with a reference to anoxic tumor cells in vitro, being nearly the same. 相似文献
12.
The effect of 0.1-5 mM misonidazole and SR 2508 on hypoxic V79 cellular survival at acute (498 cGy/min) and low (890 and 933 cGy/h) irradiation dose rates was measured and compared. The experiments were designed to delineate the oxygen mimetic phenomenon and the preincubation effect of these chemicals at these dose rates. Linear regression analysis of the survival data in terms of the linear quadratic model yielded values of alpha and beta. In the absence of drug, the linear coefficient was independent of dose rate, whereas the quadratic term was greatly reduced at low dose rate. At all dose rates, the preincubation effect affected primarily the alpha term, with little influence on beta. In contrast, the oxygen mimetic phenomenon predominantly affected the beta term. Overall, the radiosensitizing ability of these drugs was higher at low dose rate than at acute dose rate. 相似文献
13.
Using an automated low dose survival assay, the radiosensitizing effectiveness of misonidazole at low radiation dose (0-6 Gy) was measured in cultured mammalian cells. Also measured was its effectiveness at high doses of radiation (0-35 Gy) using the conventional survival assay. In both cases, several concentrations of the drug from 0 to 5 mM were used. The data at low doses were analyzed by a two-parameter mathematical equation with linear and quadratic dose terms, S = e-alpha D-beta D2, which proved to be a good fit to the experimental data at all misonidazole concentrations. It is shown that whereas the coefficient of the quadratic dose term, beta, increases significantly with increasing misonidazole concentration, the drug does not significantly affect the coefficient of the linear term, alpha. The enhancement ratio (ER) of misonidazole is shown to be decreased at lower doses. The clinical implications of this result are discussed. 相似文献
14.
N R Vepkhvadze 《Radiobiologiia》1984,24(1):92-94
A single exposure to ionizing radiation combined with the administration of metronidazole accelerated the regression of sarcoma-45 and increased the number of animals with fully regressed tumors as compared to control rats exposed to radiation alone. The maximum effect was registered when tumors were irradiated 90 min after the administration of metronidazole. With fractionated irradiation the radiosensitizing effect of metronidazole was less pronounced. 相似文献
15.
Misonidazole, a clinically-effective 2-nitroimidazole hypoxic cell radiation sensitizer, and 12 4-nitro-5-sulfonatoimidazoles were tested in cultured human SW1116 colorectal adenocarcinoma cells for radiosensitizing efficiency. Octanol-water partition coefficients and HPLC capacity factors were determined for all agents as measurements of lipophilicity, and an excellent correlation was found between the two measurements. Cytotoxicity, in vitro glutathione reactivity, and one-electron reduction potential were also determined for each compound to evaluate potential utility as macromolecularly transported radiosensitizers. Ten members of the set were found to be 40 to 300 times more radiotoxic than misonidazole, but no correlation was found between their radiosensitizing efficiencies and the chemical and physical parameters. 相似文献
16.
A Su?kowska B Lubas T Wilczok 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1984,46(2):169-179
The stability of association of nitroimidazole radiosensitizers (metronidazole and misonidazole) with bovine serum albumin (BSA) was examined in aqueous solutions by 1H n.m.r. spectroscopy in the presence of urea (0-8M) as denaturant, or high salt concentration (NaCl0-5M). A broadening of n.m.r. lines of the two radiosensitizers observed in the presence of BSA disappeared with increasing urea concentration. An especially large narrowing effect was observed for the lines attributed to the methylene group near to the hydroxyl in the side chain of misonidazole. The results suggest a release of both radiosensitizers from their binding sites on unfolding by urea of the polypeptide chain of BSA. The increase of ionic strength I caused a monotonic enhancement of broadening by BSA of the metronidazole lines. For misonidazole, the enhancement of broadening was observed at values of I greater than 1, but at low (less than 1 M) concentrations of NaCl the broadening disappeared. Thus, the results obtained in the systems with salt reflect quantitative changes in hydrophobic and hydrogen-bonded contributions to binding of aliphatic moieties of radiosensitizers to BSA. 相似文献
17.
The role of thiols in cellular response to radiation and drugs 总被引:3,自引:0,他引:3
Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme A. GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Some nitroheterocyclic radiosensitizing drugs also deplete cellular thiols under aerobic conditions. Such reactivity may be the reason that they show anomalous radiation sensitization (i.e., better than predicted on the basis of electron affinity). Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole. In conclusion, we propose an altered thiol model which includes a mechanism for thiol involvement in the aerobic radiation response of cells. This mechanism involves both thiol-linked hydrogen donation to oxygen radical adducts to produce hydroperoxides followed by a GSH peroxidase-catalyzed reduction of the hydroperoxides to intermediates entering into metabolic pathways to produce the original molecule. 相似文献
18.
Binding of two hypoxia probes, [3H]misonidazole and AF-2 (2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide), was compared in Chinese hamster V79 spheroids incubated under different oxygen concentrations. Fluorescence-activated cell sorting based on Hoechst 33342 penetration was used to obtain populations of cells from different depths within the spheroid, and sorted cells were analyzed by cytofluorometry for AF-2 content and by liquid scintillation counting for [3H]misonidazole content. The patterns of AF-2 and misonidazole binding were very similar, with about 20-fold more localization of both drugs in anoxic compared to aerobic cells. Similar results were obtained when cells were sorted on the basis of AF-2 rather than Hoechst 33342 fluorescence. When mean cellular fluorescence of AF-2 was plotted versus cpm misonidazole/cell for different oxygen tensions, it appeared that oxygen was equally effective in inhibiting AF-2 and misonidazole binding. Internal cells of anoxic spheroids bound about twice as much AF-2 and misonidazole as external cells, apparently due to an increased rate of nitroreduction by chronically hypoxic cells. AF-2 was found to enhance the retention of misonidazole in oxic and hypoxic spheroids when both drugs were present. 相似文献
19.
Nicholas Farrell Tânia M. Gomes Carneiro Frederick W.B Einstein Terry Jones Kirsten A. Skov 《Inorganica chimica acta》1984,92(1):61-66
The synthesis and properties of some nitroimidazole complexes of platinum and palladium starting from the MCl42- salts are described. Both 5-NO2-imidazole and metronidazole give cis-[MCl2L2] complexes whereas trans-[MCl2L2] is obtained for 2-NO2-imidazole and misonidazole. The crystal structure of trans-dichlorobis(misonidazole)platinum(II) was determined by three-dimensional X-ray methods. The compound crystallized in space group P21/c in discrete monomeric units with a = 11.303(5), b = 13.002(5) and c = 8.125(3) Å, B = 91.39(3)°, Z = 2 and the observed and calculated densities are 1.83 and 1.859 respectively. The final full-matrix least-squares refinement gave values of R1 = 0.037 and R2 = 0.045 for 142 variables. The complex is square-planar with Pt-Cl and Pt-N distances of 2.294(3) and 2.016(9) Å respectively. The mean plane of the misonidazole ring is twisted 56° with respect to the PtCl2L2 square plane and the Cl-Pt-N angles are 89.4(3) and 90.6(3)°; the nitro group also lies out of the plane of the misonidazole ring. The closest nonbonded contact between non-hydrogen atoms in the unit cells is 2.80 Å suggesting hydrogen bonding between the hydroxyl proton and the ether oxygen in the misonidazole side-chain, i.e. O-H?O. Aspects of the chemistry of these species in relation to their biological activity are discussed. 相似文献
20.
Generation of radical anions from metronidazole, misonidazole and azathioprine by photoreduction in the presence of EDTA 总被引:1,自引:0,他引:1
D E Moore C F Chignell R H Sik A G Motten 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1986,50(5):885-891
Ultraviolet irradiation of the nitroimidazole derivatives metronidazole, misonidazole, azathioprine and 1-methyl-4-nitroimidazole in aqueous solution with various reductants produced the respective nitro radical anions, as detected by electron spin resonance spectroscopy. The most effective reductant, yielding high concentrations of the radical anions, was EDTA at pH 10. NADH, NADPH, formaldehyde glutathione and methanol were also tested but were less efficient as reductants. 相似文献