<i>In Vitro</i>Evaluation of Some Latent Radioprotective Compounds

Vos, O.; Budke, L.; Grant, G. A.

doi:10.1080/09553007614551251

Cited by 14 publications

(4 citation statements)

References 18 publications

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“…These results further suggest that it is the sulfhydryl group or the presence of a disulfide bond that seems necessary for compounds to inhibit ST activity. Until now, research with thiols and disulfides as therapeutic agents has centered on their radioprotective properties (3,4,34,39) and their efficacy in the treatment of acetaminophen overdoses (2,11,27,35,36) and nephropathic cystinosis (38,41).…”

Section: Resultsmentioning

confidence: 99%

Reduction of the secretory response to Escherichia coli heat-stable enterotoxin by thiol and disulfide compounds

Greenberg¹,

Dunn²,

Guerrant³

1983

Infect Immun

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We examined the effects of disulfide and thiol compounds on Escherichia coli heat-stable enterotoxin (ST) and cyclic GMP-induced secretion. Both cystamine and cystine (disulfide compounds) reduced the secretory responses to submaximal doses of ST in suckling mice (at 0.5 ,umol per mouse) and reduced ST activation of guanylate cyclase (by 33 to 73% at 1 mM). In higher doses, cystamine completely eradicated a maximally effective ST dose as well. In addition, the sulfhydryl (thiol) compounds cysteamine, cysteine, and acetylcysteine strikingly reduced the secretory response and the guanylate cyclase response to ST. Neither the disulfide nor the thiol compounds tested reduced cyclic GMP-induced secretion. These studies suggest that disulfide and thiol compounds both block ST-induced secretion before its activation of guanylate cyclase. Taken with the work of others, these findings suggest that disulfide compounds may alter the oxidation reduction state of a cell or act directly on the guanylate cyclase enzyme, whereas thiol compounds may inactivate ST itself by breaking its disulfide bridges, or it may alter guanylate cyclase activation by ST. Both families of compounds deserve further consideration among potential antisecretory agents for application in the control of ST-induced diarrhea.on August 5, 2020 by guest http://iai.asm.org/ Downloaded from

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Section: Resultsmentioning

confidence: 99%

Reduction of the secretory response to Escherichia coli heat-stable enterotoxin by thiol and disulfide compounds

Greenberg¹,

Dunn²,

Guerrant³

1983

Infect Immun

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“…Like 2mercaptoethylamine, they are all actual or potential aminothiols. AET undergoes rearrangement in neutral aqueous solutions to form mercaptoethylguanidine (43); with WR2721, the phosphate group shielding the thiol can be removed by hydrolysis to yield the active compound WR1065 (34,51,54). Unlike WR1065, WR2721 was ineffective in reversing STa activation of guanylate cyclase (Table 2), and we concluded that its ineffectiveness was a result of its relatively slow rate of dephosphorylation by BBMV under the conditions of the guanylate cyclase assay.…”

Section: Discussionmentioning

confidence: 92%

“…We therefore decided not to exclude AET and BAL from in vivo testing. WR1065, WR2721, and AET were developed for chemical protection against ionizing radiation (43,54). Like 2mercaptoethylamine, they are all actual or potential aminothiols.…”

Section: Discussionmentioning

confidence: 99%

Reversal of the biological activity of Escherichia coli heat-stable enterotoxin by disulfide-reducing agents

Eldeib¹,

Dove²,

Parker³

et al. 1986

Infect Immun

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Various disulfide-reducing agents, mostly thiols and thiol precursors, were examined for their ability to reduce the disulfide bonds in the Escherichia coli heat-stable enterotoxin STa; reduction of the bonds results in loss of biological activity. The biological activity measured was the stimulation of guanylate cyclase in pig intestinal brush border membranes by STa. Nearly all of the compounds inactivated STa, although at different rates; a smaller number appreciably decreased guanylate cyclase activity when they were introduced into the reaction mixture after STa bound to its receptor. With dithiothreitol, the decrease in reaction rate was both time and concentration dependent and resulted in a reversal to basal activity. The anionic thiols were relatively ineffective in reversing activation, the neutral monothiols were moderately effective, and the aminothiols and neutral dithiols were the most effective. The order of effectiveness of the compounds was S-2-(3aminopropylamino)ethanethiol > 2,3-dimercaptopropanol = 2-aminoethylisothiuronium bromide > dithiothreitol > 2-mercaptoethylamine > ax-thioglycerol. These compounds were used in weanling pig ligatedintestinal-loop bioassays to determine if STa-induced secretion was reduced when they were injected 20 min after the STa. Instead of S-2-(3-aminopropylamino)ethanethiol we used the phosphorylated derivative S-2-(3-aminopropylamino)ethylphosphorothioic acid; this compound and 2,3-dimercaptopropanol were the only compounds that reduced STa-induced secretion and had no direct secretory or pathological effects.The heat-stable enterotoxin STa, which is secreted by pathogenic strains of Escherichia coli, induces secretory diarrhea in humans and animals (26). STa is a family of closely related peptides, each containing 18 or 19 amino acids (5, 7,31,42,48), and is probably synthesized as a 72-residue precursor (35,47). All of the deduced structures have six half-cystine residues in identical postions; a 14amino-acid analog containing the sequence has been synthesized and was even more potent than the natural toxin (6). Reduction of the disulfide linkages destroys biological activity (16,42,48).There is an STa receptor located in the brush border of the intestinal epithelium (20, 23); the brush border is also the location of the majority of mature-enterocyte guanylate cyclase (15,55). Field et al. (18), and later Rao et al. (38) and Guerrant et al. (29), showed that STa activated this brush border membrane guanylate cyclase but not other soluble or particulate guanylate cyclases (29, 38). DeJonge (14) and Rao and Field (37) recently reviewed the evidence supporting the hypothesis that this activation is the initial event leading to intestinal ion secretion. Based on this hypothesis, Greenberg et al. examined the effects of disulfide and thiol compounds on STa-induced secretion (25). The disulfide compounds cystamine and cystine, which are capable of reversibly inactivating purified lung guanylate cyclase by mixed disulfide formation (11), decreased STa activation of r...

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“…Chemical radioprotectors exert their protective effects through scavenging of free radicals[3]. A variety of compounds that act as chemical radioprotectors have been described including agents such as amifostine and other thiols,[4,5] nitroxides, [6-8] polyphenols,[9] tocols,[10] ethyl pyruvate,[11] superoxide dismutase mimetics,[12,13], melatonin and its homologues,[14] and other free radical scavengers. (reviewed in [15]).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the fullerene compound DF-1 as a radiation protector

et al. 2010

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BackgroundFullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells.MethodsIn vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for γH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry.ResultsDF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer γH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls.ConclusionsDF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.

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In VitroEvaluation of Some Latent Radioprotective Compounds

Cited by 14 publications

References 18 publications

Reduction of the secretory response to Escherichia coli heat-stable enterotoxin by thiol and disulfide compounds

Reduction of the secretory response to Escherichia coli heat-stable enterotoxin by thiol and disulfide compounds

Reversal of the biological activity of Escherichia coli heat-stable enterotoxin by disulfide-reducing agents

Evaluation of the fullerene compound DF-1 as a radiation protector

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