Detection of sulfur mustard-induced DNA modifications

Ludlum, David B.; Austin-Ritchie, Paula; Hagopian, Miasnig; Niu, Tianqi; Yu, Dong

doi:10.1016/0009-2797(94)90005-1

Cited by 89 publications

(50 citation statements)

References 5 publications

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“…In addition, attempts of using gas chromatography-mass spectrometry (GC-MS) for HETEG detection were also reported. However, the GC-MS assay failed for the poor derivation of HETEG in the presence of other bases [11]. Furthermore, there is few report of HETEG quantification by HPLC-MS approach.…”

Section: Introductionmentioning

confidence: 98%

“…Early efforts to quantify HETEG involved the use of radioactively labeled SM, such as [ 35 S]-SM, after digest and subsequent separation by HPLC, the radio-labeled HETEG was quantified by virtue of the radioactive label. By this technique, both [ 35 S]-SM and [ 14 C]-SM have been used for detection of HETEG isolated from the human blood or double-strand calf thymus DNA exposure to SM [9,11]. In this kind of procedure, the synthesis of radio-labeled agent and special precautions for proper radiochemical handling are shortcomings.…”

Section: Introductionmentioning

confidence: 98%

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A sensitive high performance liquid chromatography–positive electrospray tandem mass spectrometry method for N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine determination

Yuxia¹,

Yue²,

Q³

et al. 2011

Journal of Chromatography B

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

A sensitive high performance liquid chromatography–positive electrospray tandem mass spectrometry method for N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine determination

Yuxia¹,

Yue²,

Q³

et al. 2011

Journal of Chromatography B

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“…The severity of lesions observed after exposure to SM has emphasized the need for an efficient pharmacological antidote against its vesicating activity. The powerful alkylating activity of SM (Ludlum et al 1994;Matijasevic et al 1996Matijasevic et al , 2001Mol et al 1993) results from its conversion, in aqueous solution, to the highly electrophilic ethylene episulfonium derivative (Wormser 1991) that can be neutralized by nucleophilic agents. Some protection against SM can be achieved by glutathione derivatives (Lindsay and Hambrook 1998;Lindsay et al 1997), cysteine esters (Wilde and Upshall 1994), and a cysteine precursor (Gross et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of topical iodine containing anti-inflammatory drugs against sulfur mustard-induced skin lesions

Wormser

Sintov

Brodsky

et al. 2004

Archives of Toxicology

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Previous studies have shown the antidotal efficacy of topical iodine at 15 and 30 min post-exposure to sulfur mustard (SM). Here we demonstrate efficacy at longer intervals (20, 30, 45, and 60 min, respectively, for data) using an improved topical povidone-iodine preparation termed N66, which contains steroidal and non-steroidal anti-inflammatory agents. In the mouse, N66 reduced severity of ear edema by 43, 47, 44, and 36%; ear epidermal ulceration by 74, 58, 45, and 58%; and epidermal necrosis by 54, 34, 26, and 31% at the respective time points. A similar effect was observed with encrustation. The healing marker, grade of acanthotic area, showed dramatic increases of 39.6-, 25.3-, 20.9-, and 22-fold. Severity of the dermal parameters, acute inflammation and dermal necrosis, was reduced by 63, 34, 34, and 38% and 80, 54, 54, and 59%, respectively. In guinea pig skin, topical treatment with N66 45 min post-exposure reduced the SM-induced ulceration area by 75%. The histological parameters subepidermal microblister formation, epidermal ulceration, epidermal necrosis, and encrustation were reduced by 63, 61, 41, and 41%, respectively. The healing marker, grade of acanthotic area, was elevated by 73%. N66 induced a statistically significant reduction in two dermal markers for tissue damage: acute inflammation (33%) and dermal necrosis (48%). Reduced skin damage was also observed in areas adjacent the treated sites. The pharmacologically active components of N66 showed additive effect. These findings suggest that the povidone-iodine preparation combined with anti-inflammatory agents functions as a potent antidote against skin lesions induced by SM at relatively long intervals between exposure and treatment.

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“…The reaction with DNA leads to rapid formation of bulky monoadducts and DNA cross links (Debiak et al, 2011). The majority of DNA alkylation consists of adducts at the N7 position of guanine and N3 position of adenine, accounting for 61% and 16% of total alkylations, respectively (Ludlum et al, 1994). DNA di adducts, on the other hand, represent about 15% of SM induced DNA lesions and are formed by reaction of one SM molecule with N7 positions of two guanines in close proximity (Ludlum and Papirmeister, 1986).…”

Section: Introductionmentioning

confidence: 99%

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

et al. 2016

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Biological effects of CEES treated cells are significantly influenced by treatment protocol. Optimized protocol for the treatment of HaCaT cells with CEES. CEES induces a dose and time dependent PARylation response in HaCaT cells. CEES induced PAR formation is predominantly due to the activation of PARP1. Keywords:Poly(ADP-ribose) Poly(ADP-ribose) polymerases Sulfur mustard CEES HaCaT keratinocytes Solvent A B S T R A C T Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy.PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2 chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose and time dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the molecular mechanism of PARP1 activation and its functional consequences after mustard treatment in general.

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Detection of sulfur mustard-induced DNA modifications

Cited by 89 publications

References 5 publications

A sensitive high performance liquid chromatography–positive electrospray tandem mass spectrometry method for N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine determination

A sensitive high performance liquid chromatography–positive electrospray tandem mass spectrometry method for N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine determination

Protective effect of topical iodine containing anti-inflammatory drugs against sulfur mustard-induced skin lesions

Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions

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