Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Durand, Ralph E.

doi:10.1038/bjc.1983.58

Cited by 64 publications

(12 citation statements)

References 14 publications

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“…It has been suggested that WR-1065 can react rapidly with oxygen in the culture medium, leading to a state of transient hypoxia (Purdie et al, 1983;Durand, 1983;Biaglow et al, 1984). This could partially explain the reduction in DSB DNA damage reported in the present study.…”

Section: Double-strand Break Formationsupporting

confidence: 75%

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

Sigdestad¹,

Treacy²,

Knapp³

et al. 1987

Br J Cancer

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Summary Radiation induced DNA double strand breaks are believed to be important lesions involved in processes related to cell killing, induction of chromosome aberrations and carcinogenesis. This paper reports the effects of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation-induced DNA damage and repair in V79 cells using the neutral elution method performed at pH 7.2 or pH 9.6. WR-1065 (4mM) was added to the culture medium either 30 minutes prior to and during irradiation with Cobalt-60 gamma rays (for dose response experiments) or during the repair times tested (for DNA rejoining experiments). The results indicate that WR-1065 is an effective protector against the formation of radiationinduced double-strand breaks in DNA as measured using a neutral elution technique at either pH. The protector reduced the strand scission factors by 1.44 and 1.77 in experiments run at pH 9.6 and pH 7.2, respectively.The kinetics of DNA double-strand rejoining were dependent upon the pH at which the neutral elution procedure was performed. Unlike the results obtained with alkaline elution, rejoining of DNA breaks was unaffected by the presence of WR-1065 at either pH.

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Section: Double-strand Break Formationsupporting

confidence: 75%

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

Sigdestad¹,

Treacy²,

Knapp³

et al. 1987

Br J Cancer

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“…An important factor that has been demonstrated to exert a major influence on the extent of amifostine protection is the oxygen concentration at the time of irradiation (38,39). Several in vivo experiments have been carried out to measure the extent of normal tissue protection by amifostine over a wide range of inspired oxygen concentrations (26,33,34,36,37,40).…”

Section: Discussionmentioning

confidence: 99%

Effects of Amifostine on Radiation-induced Cardiac Damage

2003

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“…Dimethyl sulfoxide (1%) was toxic to cells by itself and also increased HSP synthesis (not shown). The only compound tested that we found effective in preventing erythrophagocytosis-induced synthesis of stress proteins was the free thiol WR-1065 (dephosphorylated from the radioprotective agent WR-2721) (27,28). WR-1065 inhibited induction of HSP70 and p32 during erythrophagocytosis (Fig.…”

mentioning

confidence: 99%

“…5). Because WR-1065 can act in thiol disulfide exchange reactions and substitute for glutathione as hydrogen donor (28), the protective effects of WR-1065 suggest a role for glutathione depletion in the induction of stress proteins during erythrophagocytosis. Indeed, one common property attributed to the various inducers of p32/heme oxygenase is reactivity toward sulfhydryl groups and depletion in cellular glutathione (18,19,29).…”

mentioning

confidence: 99%

Erythrophagocytosis induces heat shock protein synthesis by human monocytes-macrophages.

Clerget

Polla

1990

Proc. Natl. Acad. Sci. U.S.A.

103

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Exposure of cells to elevated temperatures and other environmental stresses results in the expression of specific genes encoding the so-called heat shock proteins (HSPs). Since exogenous H202 induces in human monocytes the synthesis of HSPs, and previous induction of HSPs protects these cells from oxidative hnjury, we investigated whether HSP synthesis was also induced during generation ofreactive oxygen species by the phagocyte itself during phagocytosis. As a model system, we analyzed the effects of erythrophagocytosis on protein synthesis by the human premonocytic line U937, in which phagocytosis is induced during differentiation with 1,25-dihydroxyvitamin D3. Exposure to whole erythrocytes, but not to erythrocyte ghosts, induced in the phagocytic cells only the synthesis of the 70-and 83-to 90-kDa HSPs and a 32-kDa oxidation-related stress protein identical by partial peptide mapping to heme oxygenase. The radioprotective aminothiol N-(2'-mercaptoethyl)-1,3-propanediamine (WR-1065), which can substitute for glutathione as hydrogen donor, prevented this induction. These results suggest that oxygen free radicals generated in the presence of hemoglobin-derived iron and consecutive glutathione depletion are involved in induction of stress protein synthesis during erythrophagocytosis. HSPs synthesized during phagocytosis may play a role in the phagocyte's defense mechanisms and in protective immunity.As a model system, we used the human premonocytic line U937 and phagocytosis of erythrocytes. (4), that preexposure to temperatures inducing the synthesis of HSPs partially protects monocytic cells from H202-induced cell death (5), and that in human neutrophils induction of a heat shock response by heat or cadmium is associated with an inhibition of superoxide production (6). These observations suggested potential implications of HSPs in the phagocytes' biology (7). We therefore asked the question whether HSP synthesis was also induced in association with the generation of reactive oxygen species by the phagocyte itself during phagocytosis. The analysis of the stress response in phagocytes is of particular relevance since it has been shown that several immunodominant antigens of intracellular microorganisms such as mycobacteria or plasmodia are indeed, by sequence homology, HSPs, and the potential role ofHSPs in protective immunity and/or immunopathology is an area of intense interest (8-11). Mycoplasma-free U937 cells were grown in RPMI 1640 medium (GIBCO) with 10% fetal calf serum/1% glutamine, with or without 1,25-(OH)2D3 (10 ng/ml) for 72 hr, then counted, centrifuged, and resuspended at 0.8 x 106 cells per ml in RPMI 1640 medium without methionine and incubated with or without SRBCs for 3 hr at 37°C. Peripheral blood monocytes from normal volunteers were isolated by gradient centrifugation and purified by adherence (4), and human alveolar macrophages were obtained as described (22) from bronchoalveolar lavage of lungs excised during surgery for carcinoma, then isolated by adherence, cultured, and stimul...

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Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Cited by 64 publications

References 14 publications

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

Effects of Amifostine on Radiation-induced Cardiac Damage

Erythrophagocytosis induces heat shock protein synthesis by human monocytes-macrophages.

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