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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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Structures of (A) 2-(4-amino-3-methylphenyl)benzothiazole (R=H; DF 203; NSC 674495), 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (R=F; 5F 203, NSC 703786) and (B) the lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305).
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fig1: Structures of (A) 2-(4-amino-3-methylphenyl)benzothiazole (R=H; DF 203; NSC 674495), 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (R=F; 5F 203, NSC 703786) and (B) the lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305).

Mentions: Using ab initio frontier molecular orbital (FMO) calculations, the presence or absence of exportable hydroxy metabolites of fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles can be predicted (O'Brien et al, in press). Only the 5-fluoro isomer produced a conventional dose–response following treatment of cells; indeed, oxidative metabolism at C-6 was eradicated. Thus, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is the favoured analogue for clinical consideration possessing enhanced efficacy in vitro and superior potency in vivo against human breast and ovarian tumour xenografts implanted in nude mice (Hutchinson et al, 2001; Bradshaw et al, 2002a). The lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305) has been derivatised at the exocyclic primary amine function fulfilling the criteria for a suitable prodrug. It is water soluble, chemically stable, pharmaceutically robust and undergoes rapid, quantitative bioreversion to the parent moiety in vitro and in vivo (Bradshaw et al, 2002a,2002b; Hutchinson et al, 2002) (Figure 1Figure 1


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)

Structures of (A) 2-(4-amino-3-methylphenyl)benzothiazole (R=H; DF 203; NSC 674495), 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (R=F; 5F 203, NSC 703786) and (B) the lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747538&req=5

fig1: Structures of (A) 2-(4-amino-3-methylphenyl)benzothiazole (R=H; DF 203; NSC 674495), 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (R=F; 5F 203, NSC 703786) and (B) the lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305).
Mentions: Using ab initio frontier molecular orbital (FMO) calculations, the presence or absence of exportable hydroxy metabolites of fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles can be predicted (O'Brien et al, in press). Only the 5-fluoro isomer produced a conventional dose–response following treatment of cells; indeed, oxidative metabolism at C-6 was eradicated. Thus, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is the favoured analogue for clinical consideration possessing enhanced efficacy in vitro and superior potency in vivo against human breast and ovarian tumour xenografts implanted in nude mice (Hutchinson et al, 2001; Bradshaw et al, 2002a). The lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305) has been derivatised at the exocyclic primary amine function fulfilling the criteria for a suitable prodrug. It is water soluble, chemically stable, pharmaceutically robust and undergoes rapid, quantitative bioreversion to the parent moiety in vitro and in vivo (Bradshaw et al, 2002a,2002b; Hutchinson et al, 2002) (Figure 1Figure 1

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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Related in: MedlinePlus