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

Leong CO, Gaskell M, Martin EA, Heydon RT, Farmer PB, Bibby MC, Cooper PA, Double JA, Bradshaw TD, Stevens MF - Br. J. Cancer (2003)

Bottom Line: However, treatment of cells with 10 microM 5F 203 resulted in the emergence of a new dominant adduct.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.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, University of Nottingham, UK.

ABSTRACT
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 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.

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HPLC separation of 32P-postlabelled adducts of control MCF-7 (A), MDA-MB-435 (C) and IGROV-1 (E) xenografts from untreated animals and MCF-7 (B), MDA-MB-435 (D) and IGROV-1 (F) xenografts from mice treated with 20 mg kg−1 Phortress i.p. Tumours were recovered 24 h post-treatment.
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fig6: HPLC separation of 32P-postlabelled adducts of control MCF-7 (A), MDA-MB-435 (C) and IGROV-1 (E) xenografts from untreated animals and MCF-7 (B), MDA-MB-435 (D) and IGROV-1 (F) xenografts from mice treated with 20 mg kg−1 Phortress i.p. Tumours were recovered 24 h post-treatment.

Mentions: Mice bearing sensitive MCF-7, IGROV-1 and inherently resistant MDA-MB-435 tumours s.c. in the flank were treated with 20 mg kg−1 Phortress or vehicle alone (i.p.). Guided by in vitro data (Figure 4) and the knowledge that CYP1A1 protein can clearly be detected within sensitive xenografts 24 h post-treatment (Bradshaw et al, 2002a), tumours were recovered 24 h after animals were treated and DNA extracted. HPLC detection of 32P-postlabelled adducts clearly distinguished one major and a number of minor Phortress-derived adducts in the DNA of MCF-7 xenografts (Figure 6Figure 6


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

Leong CO, Gaskell M, Martin EA, Heydon RT, Farmer PB, Bibby MC, Cooper PA, Double JA, Bradshaw TD, Stevens MF - Br. J. Cancer (2003)

HPLC separation of 32P-postlabelled adducts of control MCF-7 (A), MDA-MB-435 (C) and IGROV-1 (E) xenografts from untreated animals and MCF-7 (B), MDA-MB-435 (D) and IGROV-1 (F) xenografts from mice treated with 20 mg kg−1 Phortress i.p. Tumours were recovered 24 h post-treatment.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2747538&req=5

fig6: HPLC separation of 32P-postlabelled adducts of control MCF-7 (A), MDA-MB-435 (C) and IGROV-1 (E) xenografts from untreated animals and MCF-7 (B), MDA-MB-435 (D) and IGROV-1 (F) xenografts from mice treated with 20 mg kg−1 Phortress i.p. Tumours were recovered 24 h post-treatment.
Mentions: Mice bearing sensitive MCF-7, IGROV-1 and inherently resistant MDA-MB-435 tumours s.c. in the flank were treated with 20 mg kg−1 Phortress or vehicle alone (i.p.). Guided by in vitro data (Figure 4) and the knowledge that CYP1A1 protein can clearly be detected within sensitive xenografts 24 h post-treatment (Bradshaw et al, 2002a), tumours were recovered 24 h after animals were treated and DNA extracted. HPLC detection of 32P-postlabelled adducts clearly distinguished one major and a number of minor Phortress-derived adducts in the DNA of MCF-7 xenografts (Figure 6Figure 6

Bottom Line: However, treatment of cells with 10 microM 5F 203 resulted in the emergence of a new dominant adduct.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.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, University of Nottingham, UK.

ABSTRACT
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 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.

Show MeSH
Related in: MedlinePlus