Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo
| Autor: | Peter B. Farmer, Margaret Gaskell, Robert T. Heydon, Tracey D. Bradshaw, Patricia A. Cooper, Malcolm F. G. Stevens, John A. Double, C-O Leong, Mike C. Bibby, Elizabeth A. Martin |
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| Rok vydání: | 2003 |
| Předmět: |
Cancer Research
Time Factors Ratón Phortress Mice Nude Antineoplastic Agents Biology 2-(4-aminophenyl)benzothiazole Adduct chemistry.chemical_compound Mice breast cancer In vivo Tumor Cells Cultured Animals Humans Experimental Therapeutics Benzothiazoles neoplasms Mice nude DNA adducts Biological activity Neoplasms Experimental In vitro Disease Models Animal Thiazoles ovarian cancer Oncology Established cell line chemistry Biochemistry DNA Neoplasm Transplantation |
| Zdroj: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Popis: | 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 concentrations100 nM, adducts were detected in DNA of MCF-7 cells treated with 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203). 5F 203 (1 microM) led to the formation of one major and a number of minor adducts. However, treatment of cells with 10 microM 5F 203 resulted in the emergence of a new dominant adduct. Adducts accumulated steadily within DNA of MCF-7 cells exposed to 1 microM 5F 203 between 2 and 24 h. Concentrations of the lysylamide prodrug of 5F 203 (Phortress)or = 100 nM generated adducts in the DNA of sensitive MCF-7 and IGROV-1 ovarian cells. At 1 microM, one major Phortress-derived DNA adduct was detected in these two sensitive phenotypes; 10 microM 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 (or = 10 microM, 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. |
| Databáze: | OpenAIRE |
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