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2-(4-Aminophenyl)benzothiazoles represent a potent and highly selective class of antitumour agent. In vitro , sensitive carcinoma cells deplete 2-(4-aminophenyl)benzothiazoles from nutrient media; cytochrome P450 1A1 activity, critical for execution of antitumour activity, and protein expression are powerfully induced. 2-(4-Amino-3-methylphenyl)benzothiazole-derived covalent binding to cytochrome P450 1A1 is reduced by glutathione, suggesting 1A1-dependent production of a reactive electrophilic species. In vitro , 2-(4-aminophenyl)benzothiazole-generated DNA adducts form in sensitive tumour cells only. At concentrations >100 n M , adducts were detected in DNA of MCF-7 cells treated with 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203). 5F 203 (1 μ M ) led to the formation of one major and a number of minor adducts. However, treatment of cells with 10 μ M 5F 203 resulted in the emergence of a new dominant adduct. Adducts accumulated steadily within DNA of MCF-7 cells exposed to 1 μ M 5F 203 between 2 and 24 h. Concentrations of the lysylamide prodrug of 5F 203 (Phortress) ≥100 n M generated adducts in the DNA of sensitive MCF-7 and IGROV-1 ovarian cells. At 1 μ M , one major Phortress-derived DNA adduct was detected in these two sensitive phenotypes; 10 μ M Phortress led to the emergence of an additional major adduct detected in the DNA of MCF-7 cells. Inherently resistant MDA-MB-435 breast carcinoma cells incurred no DNA damage upon exposure to Phortress (⩽10 μ M , 24 h). In vivo , DNA adducts accumulated within sensitive ovarian IGROV-1 and breast MCF-7 xenografts 24 h after treatment of mice with Phortress (20 mg kg −1 ). Moreover, Phortress-derived DNA adduct generation distinguished sensitive MCF-7 tumours from inherently resistant MDA-MB-435 xenografts implanted in opposite flanks of the same mouse.

Objective Investigation of increased oxidative stress in early pregnancy and association with an increased risk of small-forgestational-age (SGA) fetus.Design Longitudinal case-control study.Setting University Hospitals of Leicester NHS Trust, Leicester, UK.Population Low-risk pregnant women with no current or preexisting medical illness were recruited at a large teaching hospital from 2004 to 2006.Methods Recruitment performed at the time of the dating ultrasound scan (12 ± 2 weeks of gestation). Spot urine samples collected at 12 ± 2 and 28 ± 2 weeks of gestation were analysed for 8-oxo-7,8-dihydro-2#-deoxyguanosine (8-oxodG) by liquid chromatography with tandem mass spectrometry). SGA was defined as birthweight <10th centile based on customised centile calculator (www.gestation.net). This identified the cases (n = 55), whereas controls (n = 55) were mothers whose babies were appropriate for gestational age (AGA, birthweight 10th-90th centile). Statistical analysis was performed using GraphPad Prism v.5. The relationship between maternal urinary 8-oxodG at different gestations and customised SGA was investigated by nonparametric tests.Main outcome measures Customised SGA and AGA pregnancies.Results Urinary 8-oxodG concentrations were significantly increased in pregnancies with subsequent SGA compared with concentrations in normal pregnancies; 12 weeks: 2.8 (interquartile range [IQR] 1.96-3.67) versus 2.2 (IQR 1.26-3.28) pmol 8-oxodG/ mmol creatinine (P = 0.0007); 28 weeks: 2.21 (IQR 1.67-3.14) versus 1.68 (IQR 1.16-2.82) pmol 8-oxodG/mmol creatinine (P < 0.0002). Concentrations decreased significantly between week 12 and 28 (P = 0.04 and P = 0.02 for controls and cases).Conclusions In this study, urinary 8-oxodG at 12 and 28 weeks were elevated in SGA compared with AGA pregnancies. This may reflect early placental changes predating clinical features of SGA.Keywords 8-oxo-7, 8-dihydro-2#-deoxyguanosine, DNA damage, fetal growth restriction, oxidative stress, placenta, pregnancy.Please cite this paper as: Potdar N, Singh R, Mistry V, Evans M, Farmer P, Konje J, Cooke M. First-trimester increase in oxidative stress and risk of small-forgestational-age fetus. BJOG 2009;116:637-642.

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Styrene oxide, which is the genotoxically active metabolite of styrene, reacts in vivo with carboxylic acid residues in hemoglobin forming phenylhydroxyethyl esters. Mild alkali hydrolysis cleaves these ester adducts, yielding styrene glycol, which in human blood labelled in vitro with 14C-styrene oxide accounted for 15% of the total radioactivity covalently bound to the protein. A quantitative assay procedure has been developed for measuring the base released styrene glycol in globin. The method utilizes solvent extraction followed by trimethylsilyl ether derivatization and separation and quantitation by capillary gas chromatography with selective ion recording mass spectrometry. Globin labelled in vitro with d8-styrene oxide was used as the internal standard. The method was used to establish a dose-response relationship in rats given single i.p. doses of styrene oxide (83.3-833 mumol/kg body wt). The method, which allows quantitation of the adducts down to levels of 15 pmol/g globin, has the potential to act as a dosimeter for industrial workers exposed to styrene or styrene oxide.