Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo

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 IAI 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 IAI is reduced by glutathione, suggesting I A I-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 nM, adducts were detected in DNA of MCF-7 cells treated with 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203). 5F 203 (1 pm) led to the formation of one major and a number of minor adducts. However, treatment of cells with 10 muM 5F 203 resulted in the emergence of a new dominant adduct. Adducts accumulated steadily within DNA of MCF-7 cells exposed to I muM 5F 203 between 2 and 24 h. Concentrations of the lysylamide prodrug of 5F 203 (Phortress) greater than or equal to 100 nM generated adducts in the DNA of sensitive MCF-7 and IGROV-I ovarian cells. At I muM, one major Phortress-derived DNA adduct was detected in these two sensitive phenotypes; 10 muM 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 (less than or equal to 10 muM, 24h). In vivo, DNA adducts accumulated within sensitive ovarian IGROV-I and breast MCF-7 xenografts 24h after treatment of mice with Phortress (20 mg kg(-1)). Moreover, Phor-tress-derived DNA adduct generation distinguished sensitive MCF-7 tumours from inherently resistant MDA-MB-435 xenografts implanted in opposite flanks of the same mouse. (C) 2003 Cancer Research UK.