Reactions of DNA bases with the anti-cancer nitrogen mustard mechlorethamine: A quantum chemical study

Pk, Shukla; Mishra, P. C.; Suhai, Sándor

doi:10.1016/j.cplett.2007.10.072

Cited by 29 publications

(24 citation statements)

References 26 publications

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“…Both SM and NM belong to the category of vesicating agents and are believed to exhibit similar mechanism/s of toxicity (Saladi, Smith, 2006, Sharma et al, 2008, Ucar et al, 2007), which could be attributed to their high reactivity and alkylating properties, mainly due to the alkylation of DNA at N-7 position of guanine (Batal et al, 2014, Guainazzi et al, 2010, Rutman et al, 1969, Shukla et al, 2007) resulting in DNA strand breaks, and if unrepaired, this may eventually lead to cell death (Kehe et al, 2009a, Kehe et al, 2008b, Kehe and Szinicz, 2005, Malaviya et al, 2010). Alkylation is mediated by cyclic sulphonium ion in case of SM and cyclic immonium ion in case of NM (Price, 1958).…”

Section: Introductionmentioning

confidence: 99%

Topical nitrogen mustard exposure causes systemic toxic effects in mice

Goswami

Kumar

Tewari‐Singh

et al. 2015

Experimental and Toxicologic Pathology

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Vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) are reported to be easily absorbed by skin upon exposure causing severe cutaneous injury and blistering. Our studies show that topical exposure of NM (3.2 mg) onto SKH-1 hairless mouse skin, not only caused skin injury, but also led to significant body weight loss and 40–80 % mortality (120 h post-exposure), suggesting its systemic effects. Accordingly, further studies herein show that NM exposure initiated an increase in circulating white blood cells by 24 h (neutrophils, eosinophils and basophils) and thereafter a decrease (neutrophils, lymphocytes and monocytes). NM exposure also reduced both white and red pulp areas of the spleen. In the small intestine, NM exposure caused loss of membrane integrity of the surface epithelium, abnormal structure of glands and degeneration of villi. NM exposure also resulted in the dilation of glomerular capillaries of kidneys, and an increase in blood urea nitrogen/creatinine ratio. Our results here with NM are consistent with earlier reports that exposure to higher SM levels can cause damage to the hematopoietic system, and kidney, spleen and gastrointestinal tract toxicity. These outcomes will add to our understanding of the toxic effects of topical vesicant exposure, which might be helpful towards developing effective countermeasures against injuries from acute topical exposures.

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Section: Introductionmentioning

confidence: 99%

Topical nitrogen mustard exposure causes systemic toxic effects in mice

Goswami

Kumar

Tewari‐Singh

et al. 2015

Experimental and Toxicologic Pathology

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“…Toxic effects of mustard agents are attributed to their alkylating nature, specifically causing DNA damage (Guainazzi et al 2010; Rutman et al 1969; Shukla et al 2007). If DNA damage is not repaired in a timely manner, this could lead to cell death or mutations (Kehe et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin

et al. 2013

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Bifunctional alkylating agent sulfur mustard (SM) and its analog nitrogen mustard (NM) cause DNA damage leading to cell death, and potentially activating inflammation. Transcription factor p53 plays a critical role in DNA damage by regulating cell cycle progression and apoptosis. Earlier studies by our laboratory demonstrated phosphorylation of p53 at Ser15 and an increase in total p53 in epidermal cells both in vitro and in vivo following NM exposure. To elucidate the role of p53 in NM-induced skin toxicity, we employed SKH-1 hairless mice harboring wild type (WT) or heterozygous p53 (p53+/−). Exposure to NM (3.2 mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/− mice at 24 h. However, by 72 h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/− mice. Myeloperoxidase activity data showed that neutrophil infiltration was strongly enhanced in NM-exposed WT mice at 24 h persisting through 72 h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72 h after exposure in p53+/− mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/− mice. Together, these data indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway could be a novel strategy for developing countermeasures against vesicants-induced skin injury.

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“…Inhibition of both the MPC and Complex II explain the effect of LND on tumor respiration that produces the selective effect of this drug on tumor energy status. Selective tumor acidification enhances the activities of nitrogen mustard alkylating agents by a complex mechanism that has been described extensively (40)(41)(42)(43)(44)(45)(46) that involves stabilizing the alkylating intermediate aziridinium cation, which is degraded by OH -ions; inhibition of glutathione transferase activity also neutralizes aziridinium cation intermediates and acid inhibition of O 6 -alkyltransferase also called O 6 -methylguanine transferase (MGMT), a key enzyme involved in repair N-mustard alkylation of DNA at the N 7 and O 6 positions of guanine, also contributes to acid potentiation of N-mustard antineoplastic activity. Potentiation of doxorubicin activity appears to occur by a cation-trapping mechanism; the neutral weakly basic form of doxorubicin crosses the plasma membrane and is trapped in the tumor cell as a result of protonation in the acidified cytosol.…”

Section: Discussionmentioning

confidence: 99%