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At least 613 records · Page 34Linked to original sources
PubMed1975

Evaluation of radiochemical protectors using urinary deoxycytidine levels.

It is customary to use the LD50 response as a criterion for the evaluation of chemical radioprotection. The increased urinary excretion of deoxycytidine (CdR) in irradiated rats has been shown to be a linear dose--response relationship up to 200 R, thus making it possible to consider such a response as a criterion for chemical radioprotection evaluation at sub-lethal irradiation levels. Rats were subjected to 200 R X-irradiation with various chemical protectors and without chemical protectors, urine was collected 24 hours after irradiation, and the CdR levels in the urine analysed. A dose-reduction factor (DRF) was determined for 24-hour urinary excretions of CdR for chemically protected and non-protected rats. The DRF values are within 6 per cent of those reported by other investigators using LD50 as the response criterion for serotonin, cysteine, MEA and PAPP but differ for WR-2721 and WR-2823. Agreement using WR-2721 and WR-2823 compounds is only obtained when the toxicity effect of the compound is taken into consideration.

Animals↗
PubMed1976

In vitro evaluation of some latent radioprotective compounds.

In tissue culture, protection against X-irradiation by a number of cysteamine derivatives was studied and the results were compared with data obtained in mice. Compounds with a covered SH group, like WR 638, cysteamine phosphate, WR 2721, and AE 48527, showed practically no protection when dissolved in tissue-culture medium, but developed a protective activity when dissolved in rat blood. Thiol measurements demonstrated that in rat blood the compounds were partly hydrolysed to thiols. C511 was also hydrolysed in culture medium and was slightly less effective than cysteamine in culture medium. Cysteamine phosphate was hydrolsed more easily than cysteamine sulphate and the protective activity in rat blood was better. WR 2721 was also partly hydrolysed in rat blood. The in vitro protection of this compound was disappointing when compared with results in vivo. Its SH form (WR 1065) also showed less protection than expected from in vivo experiments. Thus, the little protection by WR 2721 in vitro in rat blood is not only due to its incomplete conversion into its thiol. Longer incubation times and the use of rat blood as a solvent brought the protective activity of WR 1065 almost up to the level of cysteamine. This may indicate that WR 1065 penetrates the cells poorly. WR 1065 was the only compound we studied whose protective activity in vitro was improved appreciably by dissolving it in rat plasma.

Amifostine↗
PubMed1977

Effect of oxygen on bacteria and cultured mammalian cells irradiated in the frozen state.

The oxygen effect for bacteria and cultured mammalian cells at -196 degrees C was studied, using suspensions to which were added cryoprotective and chemical protective agents. The oxygen enhancement ratio (o.e.r.) in the frozen state was dependent on the chemicals added to the suspensions. When the chemicals had a high competitive reactivity with oxygen to the damage, the o.e.r. in the frozen state was comparable to that in the liquid suspensions. Without chemicals, the o.e.r. in the frozen state decreased significantly, probably because of the low competitive activity of endogenous SH compounds. In general, the systems with a higher o.e.r. in the liquid state had a lower o.e.r. in the frozen state.

Cell Survival↗
PubMed1983

Interaction of cultured mammalian cells with WR-2721 and its thiol, WR-1065: implications for mechanisms of radioprotection.

An isothermal microcalorimeter was used to measure changes in heat flow when radioprotective drugs were added to cultured mammalian cells. The heat produced when WR-2721 was added continued for at least 90 min. WR-2721 was dephosphorylated by the cells to thiol (WR-1065) which oxidizes to disulphide. In the microcalorimeter, thiols give an immediate burst of heat due to this oxidation. A biological oxygen monitor revealed that WR-1065 and cysteamine rapidly consumed all the oxygen in culture medium. (10 mM WR-1065 deoxygenated medium in 2 min.) Rapid consumption of oxygen by radioprotective thiols indicates that they will not co-exist with oxygen for long in cells. This has two important implications with respect to mechanisms of radioprotection: (1) oxygen in tissues will be consumed rapidly and could result in local hypoxia; and, (2) at modest doses of protective agents the thiol will be consumed in oxic cells and hence very little will be available for reactions such as hydrogen donation. Our results indicate that anoxia is probably the principal mechanism of protection by aminothiols in mammals and aerated cells. This has major implications for clinical applications of radioprotectors and these are discussed.

Amifostine↗
PubMed1983

WR-2721, its derivatives and their radioprotective effects on mammalian cells in culture.

Although it is well known that WR-2721 is very efficient in protecting mice against lethal irradiation, we could not find any radioprotective effect of WR-2721 on mouse L cells in culture. But WR-1065 alone (free SH form of WR-2721), and WR-2721 pre-incubated with mouse liver homogenate, showed radioprotective ability. It was found that mouse liver homogenate dephosphorylated WR-2721 to WR-1065. The highest WR-2721 metabolizing activity was found in mouse liver homogenate and Chang liver cell homogenate. Homogenates of human liver and kidney were also shown to possess moderate activity for metabolizing WR-2721. These results suggest to us that WR-2721 must be dephosphorylated before exerting its radioprotective effect and that this dephosphorylating activity varies with tissues. It is demonstrated therefore that mouse L cell in culture is a novel system to assess the extent of dephosphorylation of WR-2721 in various tissues.

Aged↗
PubMed1990

The effect of the radioprotector WR-2721 and WR-1065 on mitochondrial lipid peroxidation.

The radioprotective agent WR-2721 is dephosphorylated to the free thiol form WR-1065 in vivo. The effects of WR-2721, WR-1065 and reduced glutathione on a mitochondrial lipid peroxidation system were compared. WR-2721 had no effect on mitochondrial lipid peroxidation in vitro, and could not prevent the inactivation of mitochondrial enzymes. Both WR-1065 and glutathione were effective inhibitors of mitochondrial lipid peroxidation induced by ADP/Fe/NADPH or by ADP/Fe/ascorbate. Both thiols correspondingly delayed the free radical-mediated inactivation of succinate dehydrogenase and isocitrate dehydrogenase. WR-1065 was able to reduce cumene hydroperoxide non-enzymatically, and proved to be weak substrate for glutathione peroxidase. The disulfide formed from WR-1065 could be reduced by glutathione without the participation of glutathione reductase. A redox cycle is proposed between WR-1065, glutathione and glutathione reductase to explain the inhibitory effect of WR-1065 on lipid peroxidation.

Amifostine↗
PubMed1991

The effects of counter-ion condensation and co-ion depletion upon the rates of chemical repair of poly(U) radicals by thiols.

Bimolecular rate constants for reactions of poly(U) radicals with a series of thiols of varying net charge (Z) were measured by pulse radiolysis with conductivity detection at low ionic strength. At pH 7 and 18 degrees C the values of k2 (M-1s-1) were: reduced glutathione (Z = -1), less than 500; 2-mercaptoethanesulphonic acid (Z = -1), 1.5 x 10(3); 2-mercaptoethanol (Z = 0), 1.8 x 10(5); cysteine (Z = 0), 2.0 x 10(5); cysteamine (Z = +1), 4.1 x 10(7). Values determined at pH 4 were: 2-mercaptoethanol, 6.1 x 10(5); cysteamine 2.2 x 10(8); N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065, Z = +2), 4.6 x 10(8). The variation in rate with structure could not reasonably be attributed to inherent reactivity differences in the thiols and was ascribed to inhomogeneous distributions of the thiols in solution resulting from electrostatic interactions. Thus, cationic thiols are concentrated approximately 100-fold near poly(U), relative to neutral thiols, as a consequence of counter-ion condensation, whereas anionic thiols have approximately 100-fold lower concentration near poly(U) than neutral thiols as a result of co-ion depletion. These results show that the ability of a thiol to repair radical sites in a polyanion is dramatically influenced by its net charge as a consequence of the counter-ion condensation and co-ion depletion phenomena.

Cysteamine↗
PubMed1993

Effects of WR-1065 and WR-151326 on survival and neoplastic transformation in C3H/10T1/2 cells exposed to TRIGA or JANUS fission neutrons.

We demonstrated the ability of aminothiols WR-1065 and WR-151326, each at concentration 1 mM, to protect C3H/10T1/2 cells against the transforming effects of fission neutrons under two distinct sets of experimental conditions. Experiments with WR-1065 were performed with stationary cultures of C3H/10T1/2 cells, and a TRIGA reactor-generated fission neutron field at the Armed Forces Radiobiology Research Institute (USA). Experiments with WR-151326 were performed with proliferating cultures of C3H/10T1/2 cells and a JANUS reactor-generated fission neutron field at the Argonne National Laboratory (USA). Radioprotectors were present before, during, and after irradiation for total-periods of 35 min (WR-151326; 10 min pre-incubation) or 1 h (WR-1065; 30 min pre-incubation). Bioavailability of WR-1065 and WR-151326 in extracellular medium under experimental conditions simulating those of the transformation experiments was studied by measuring oxidation rates in the presence of attached C3H/10T1/2 cells in plateau and exponential phase of growth for periods of up to 5 h. Estimated half-lives for autoxidation of WR-1065 or WR-151326 were approximately 8 min or 1 h regardless of the proliferative status of cells. In the absence of WR-compounds, dose-response data for transformation induction by neutrons from TRIGA and JANUS reactors were fitted to a common curve with a linear coefficient of about 7 x 10(-4)/Gy. WR-151326 and WR-1065 were found to provide significant radioprotection by factors of 1.79 +/- 0.08 and 3.23 +/- 0.19, respectively, against fission neutron-induced neoplastic transformation. No significant protection against neutron-induced cell lethality was observed.

Animals↗
PubMed1993

Relationships between DNA damage and the survival of radiosensitive mutant Chinese hamster cell lines exposed to gamma-radiation: Part 2. Effect of cellular redox status.

To characterize further the nature of the defects underlying the differential radiosensitivities of the Chinese hamster ovary cell lines NM2, EM9, and UV41, we compared the abilities of anoxia and of the thiol WR-1065 to protect these mutants and their parent cell line, AA8, from the lethal effects of gamma-radiation. Wide differences in oxygen enhancement ratios (OERs) for cell killing were observed in the different cell lines, those for UV41 and NM2 cells (1.8 and 2.1, respectively) being reduced and that for EM9 cells (3.3) being slightly (although significantly) increased compared with wild-type AA8 cells (2.9). These OER data support the hypothesis that repair-deficient mutants are hypersensitive to radiation under redox conditions that favour the formation of the particular lesions that correspond to their repair defect, and also support the earlier suggestion that the underlying molecular bases of the radiosensitivity of EM9 and NM2 cells are very different. In contrast to protection by anoxia, a 30-min preirradiation treatment with WR-1065 (4 mmol dm-3) protected aerated AA8, EM9, NM2, and UV41 cells to a similar extent with respect to both cell killing and the efficiency of DNA double-strand break (dsb) induction as measured by neutral elution. This observation is in marked contrast with reports of a greatly reduced protection by thiols for some repair-deficient cell lines and with the above-mentioned anoxia data. Thus, the particular types of mutations characteristic of NM2, EM9, and UV41 cells that give rise to their unusual OERs have little impact on the ability of WR-1065 to modify either cell killing or dsb induction, supporting radiochemical evidence that the types of deoxyribose radicals modifiable by oxygen and thiols are qualitatively different. Furthermore, because the extent of protection of these CHO mutants by thiols and anoxia show no correlation, oxygen depletion cannot be a major component of protection of aerated cells by thiols under these conditions.

Animals↗
PubMed1993

Influence of intracellular thiol and polyamine levels on radioprotection by aminothiols.

We examined the effect of manipulating the levels of two endogenous radioprotectors, glutathione (GSH) and polyamines, on the ability of exogenous aminothiols to protect Chinese hamster ovary cells from the lethal effects of gamma-radiation. Treatment with 0.5 mmol dm-3 buthionine sulfoximine (BSO) for 24 h depleted GSH levels to < 1% of control and significantly sensitized the cells to irradiation in air. Undepleted control cells were protected by WR-1065 (4 mmol dm-3; 30-min preirradiation treatment at 37 degrees C) by 2.09-fold (range 1.98-2.21) at the 10% survival level, whereas BSO-treated cells were protected by a factor of 1.98 (range 1.95-2.14) at this survival level. Thus, GSH depletion had no significant effect on the radioprotective capacity of WR-1065. Treating cells with 1 mmol dm-3 alpha-difluoromethyl ornithine (DFMO) for 48 h depleted the polyamines putrescine and spermidine to very low levels, while spermine was not significantly depleted. DFMO also sensitized cells to aerobic irradiation. WR-1065 protected DFMO-treated cells by 2.29-fold (range 2.08-2.53), whereas undepleted control cells were protected by 2.09-fold (range 1.98-2.21) at the 10% survival level. Thus, WR-1065 appeared to offset the radiosensitizing effect of the DFMO treatment. Cysteamine, on the other hand, protected control and DFMO-treated cells to the same extent. We also examined the effect of combinations of exogenous thiols on radiosensitivity. Cells were treated with WR-1065 (4 mmol dm-3) for 30 min and then with increasing concentrations of dithiothreitol for 5 min prior to irradiation. The protective effects of these two thiols were simply additive.

Animals↗
PubMed1994

Correlation between gamma-ray-induced DNA double-strand breakage and cell killing after biologically relevant doses: analysis by pulsed-field gel electrophoresis.

We examined the degree of correlation between gamma-ray-induced lethality and DNA double-strand breaks (dsbs) after biologically relevant doses of radiation. Radiation lethality was modified by treating 14C-labelled Chinese hamster ovary cells with either of two aminothiols (WR-1065 or WR-25591) and the associated effect on dsb induction was determined by pulsed-field gel electrophoresis (PFGE). The use of phosphorimaging to analyse the distribution of 14C-activity in the gel greatly improved the low-dose resolution of the PFGE assay. Both WR-1065 and WR-25591 protected against dsb induction and lethality to a similar extent after low doses of radiation, although this correlation broke down when supralethal doses were used to induce dsbs. Thus, the level of dsbs induced in these cells as measured by PFGE after survival-curve doses of gamma-radiation is consistently predictive of the degree of lethality obtained, implying a case-effect relationship between these two parameters and confirming previous results obtained using the neutral filter elution assay for dsbs.

Animals↗
PubMed1997

Modulation of radiation-induced apoptosis by thiolamines.

Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8.3 hybridoma after a 60-min (LD50 = 4.5 mM) or during a 20-h (LD50 = 0.15 mM) exposure. In contrast, a 20-h exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50% apoptosis within 20 h. Apoptosis was not induced by either a 60-min or 20-h exposure to 10 mM of the thiazolidine prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4 mM for 15 min) or cysteine (10 mM for 60 min) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 h) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 min beginning 60 min after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 h beginning 60 min after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

Animals↗