Glutathione and N-acetylcysteine conjugates of 2-chloroethyl isocyanate. Identification as metabolites of N,N'-bis(2-chloroethyl)-N-nitrosourea in the rat and inhibitory properties toward glutathione reductase in vitro

Davis, Margaret R.; Kassahun, Kelem; Jochheim, Claudia M.; Brandt, Kathleen M.; Baillie, Thomas A.

doi:10.1021/tx00033a020

Cited by 46 publications

(41 citation statements)

References 29 publications

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“…[5,14,17] Analysis of BCNU has been a challenge because of its instability in solution. [6] As mentioned in the introduction, there are several analytical methods in the literature which either require derivatization or the use of deuterated isotopes. A simple LC-MS method would offer a significant advantage for the day-to-day routine analysis of BCNU.…”

Section: Resultsmentioning

confidence: 99%

“…[5] It decomposes under physiological conditions and one of the decomposition products (alkylating agent) is the proposed active molecule. [6,7] Previously reported analytical methods for the analysis of BCNU include a colorimetric assay, [8] high performance liquid chromatography coupled with a UV detector, [9] chemical ionization mass spectrometry analysis. [10] and gas chromatography coupled with various detectors including mass spectrometry and an electron capture detector.…”

Section: Introductionmentioning

confidence: 99%

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A Simple and Sensitive Apci-Lc-MS Method for the Detection of the Antitumor Agent, Carmustine (Bcnu) in Rat Plasma

Kate

Kohl

Kerr

2010

Journal of Liquid Chromatography & Related Technologies

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& A simple and sensitive LC-MS method for the quantitative determination of the antitumor agent, N,N 0 -bis (2-chloroethyl)-N-nitrosourea (BCNU or carmustine), is described in this report. The method has been developed using an atmospheric pressure chemical ionization (APCI) probe on an ion trap mass spectrometer. A formate adduct ([M þ 45] À ) of BCNU was observed in the negative mode at 257.8 m=z and further confirmation for BCNU was obtained by observing the characteristic isotopic pattern in the mass spectrum, which indicated the compound contained two chlorine atoms. The extraction of BCNU from rat plasma with isopropyl ether:hexane (1:1) resulted in 81.3% of sample recovery. The limit of detection (LOD) calculated for the method was 1.25 ng (injected amount) using a standard solution of BCNU (S=N ¼ 9:1). Optimum linearity and reproducibility data were obtained for BCNU; r 2 ¼ 0.9999 (0.2 mg=mL to 10.2 mg=mL) with precision of (RSD) 6.4% at two different concentrations and accuracy of 92.3 and 102.4%.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Simple and Sensitive Apci-Lc-MS Method for the Detection of the Antitumor Agent, Carmustine (Bcnu) in Rat Plasma

Kate

Kohl

Kerr

2010

Journal of Liquid Chromatography & Related Technologies

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“…Carmustine metabolite, chloroethyl isocyanate, carbamylates TR molecule and creates an irreversible inactivation of this enzyme in vivo and in vitro (Davis et al, 1993). Redox processes occurring in living organisms, among other things, to eliminate and repair damages caused by hydrogen peroxide, reduction of semiascorbate radical, and dehydroascorbate radical, as well as regulation of p53 protein activity, are also controlled by the thioredoxin system (Handley and Sunde, 2001;Smart et al, 2004;Spector et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Comparison of influence of carmustine and new proline analog of nitrosourea on antioxidant system in breast carcinoma cells (MCF-7)

Stankiewicz-Kranc

Miltyk

Skrzydlewska

2009

Drug and Chemical Toxicology

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The high toxicity and low selectivity of carmustine restrict its application in anticancer therapy. Therefore, proline analogs of nitrosourea have been synthesized to obtain compounds whose action on neoplastic cells is characterized by higher selectivity. The present studies have aimed at examining the influence of carmustine and a new proline analog of nitrosourea on the redox system of fibroblasts and breast cancer cells (MCF-7). Carmustine and the proline analog of nitrosourea caused an increase in hydrogen peroxide concentration both in fibroblasts and MCF-7 cells. Moreover, administration of carmustine and the new analog of nitrosourea caused a decrease in the activity of antioxidant enzymes. Observed changes in the antioxidant system correlated with an increase in concentration of dityrosine, as well as a decrease in tryptophan concentration. Changes in the antioxidant system were also accompanied by intensification of the lipid peroxidation process. In conclusion, carmustine and proline analog of nitrosourea produce similar changes in the antioxidant system in normal and cancer cells and are responsible for oxidative stress.

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“…Electrospray is a desirable ionization method for coupling between liquid chromatography and MS, [90][91][92][93][94][95][96][97][98] because it easily transforms target molecules in solution to gas-phase ions at atmospheric pressure. The physico-chemical properties of the The ionization efficiency is based on the relationship between the properties of ionic groups in the target molecule and the pKa value of the acidic component of the salt added to the mobile phase.…”

Section: ·1 Electrospray Ionizationmentioning

confidence: 99%

Biomedical and Biological Mass Spectrometry

Mano

Goto

2003

ANAL. SCI.

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By the end of the 20th century, mass spectrometry (MS) had evolved drastically as a major analytical tool in biomedical and biological research. Recent mass spectrometers, designed for ease of handling, came into wide use in the 1990s. Soft ionization methods, which were made practical in the second half of the 1980s, allowed for the sensitive analysis of nonvolatile and thermolabile compounds by MS. Electrospray ionization (ESI) 1,2 and matrix-assisted laser desorption ionization (MALDI) 3 methods, made it possible to ionize large biomolecules and to transfer them to the gas phase, thereby becoming a valuable tool in both protein and peptide analysis [4][5][6] and in the study of drugs and their metabolites [7][8][9][10][11][12] in the human body. Many reviews of MS have recently been published, [13][14][15][16][17][18][19] and in particular, the number of reviews describing biochemical, biological, and biomedical MS have increased dramatically over the last ten years. Initially, there were many commentary reviews on new techniques, such as soft ionization methods and mass analyzers, 13-15 and more recently, review articles have focused on the biological and biomedical applications of MS. 18-21 Above all, two major fields, drug discovery and proteomics, have made marked advances based on MS.Articles in the MEDLINE database were searched, and the results are illustrated in Fig. 1 and Table 1. Over the last 15 years, a total of 79220 MS articles were placed in the database, with a 2.5-fold increase from 1987 to 1999. The number of articles using fast atom bombardment (FAB) as an ionization method remained almost constant during this period. This ionization method is a practical soft ionization procedure, which was applied to the analysis of peptides [22][23][24][25][26][27][28][29][30][31] and endogenous biological substances [32][33][34][35] in the 1980s. Atmospheric pressure chemical ionization (APCI) is a suitable method 36 for the ionization of middle or weakly polar low-molecular-weight molecules, and can be easily coupled to conventional highperformance liquid chromatography (HPLC), used at a flow rate of around 1 mL/min. [37][38][39][40][41][42][43][44][45][46][47][48] However, the number of articles concerning APCI have increased slowly, because most drugs developed recently contain polar groups which can be ionized without difficulty by the ESI technique. Japan This review focuses on biological and biomedical mass spectrometry, and covers a selection of publications in this area included in the MEDLINE database for the period 1987 -2001. Over the last 15 years, biological and biomedical mass spectrometry has progressed out of all recognition. The development of soft ionization methods, such as electrospray ionization and matrix-assisted laser desorption ionization, has mainly contributed to the remarkable progress, because they can easily produce gas-phase ions of large, polar, and thermally labile biomolecules, such as proteins, peptides, nucleic acids and others. The innovations of ionization meth...

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Glutathione and N-acetylcysteine conjugates of 2-chloroethyl isocyanate. Identification as metabolites of N,N'-bis(2-chloroethyl)-N-nitrosourea in the rat and inhibitory properties toward glutathione reductase in vitro

Cited by 46 publications

References 29 publications

A Simple and Sensitive Apci-Lc-MS Method for the Detection of the Antitumor Agent, Carmustine (Bcnu) in Rat Plasma

A Simple and Sensitive Apci-Lc-MS Method for the Detection of the Antitumor Agent, Carmustine (Bcnu) in Rat Plasma

Comparison of influence of carmustine and new proline analog of nitrosourea on antioxidant system in breast carcinoma cells (MCF-7)

Biomedical and Biological Mass Spectrometry

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