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DNA damage and cell cycle arrest induced by 2-(4-amino-3- methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells

  1. Author:
    Trapani, V.
    Patel, V.
    Leong, C. O.
    Ciolino, H. P.
    Yeh, G. C.
    Hose, C.
    Trepel, J. B.
    Stevens, M. F. G.
    Sausville, E. A.
    Loaiza-Perez, A. I.
  2. Author Address

    NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, 9000 Rockville Pike,Blgd 10,Rm 6N115, Bethesda, MD 20892 USA NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA Univ Nottingham, Sch Pharmaceut Sci, Nottingham NG7 2RD, England Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA Natl Canc Inst, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Canc Res Ctr,NIH, Frederick, MD 21702 USA NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Frederick, MD 21702 USA NCI, Med Oncol Clin Res Unit, Med Branch, NIH, Bethesda, MD 20892 USA Loaiza-Perez AI NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, 9000 Rockville Pike,Blgd 10,Rm 6N115, Bethesda, MD 20892 USA
    1. Year: 2003
  1. Journal: British Journal of Cancer
    1. 88
    2. 4
    3. Pages: 599-605
  2. Type of Article: Article
  1. Abstract:

    The fluorinated benzothiazole analogue 2-(4-amino-3- methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is a novel agent with potent and selective antitumour properties and, in the form of its L-lysylamide prodrug Phortress (NSC 7 10305), is a current candidate for early phase clinical studies. Previous findings have indicated that cytochrome P450 IAI (CYPIAI) may play a role in the antitumour activity of molecules in the benzothiazole series including the nonfluorinated parent compound 2-(4-amino- 3methyiphenyl)benzothiazole (DF 203, NSC 674495) (Kashiyama et al, 1999; Chua et a, 2000; Loaiza-Perez et a], 2002). In this study, we assessed and verified that a fully functional aryl hydrocarbon receptor (AhR) signalling pathway is a necessary requisite for the induction of efficient cytotoxicity by 5F 203 in MCF-7 wild-type sensitive cells. Drug exposure caused MCF-7 sensitive cells to arrest in G I and S phase, and induced DNA adduct formation, in contrast to AhR-deficient AhR-deficient AHR(100) MCF-7 cells. In sensitive MCF-7 cells, induction of CYPIAI and CYPIBI transcription (measured by luciferase reporter assay and real-time reverse transcriptasepolymerase chain reaction (RT-PCR)), and 7-ethoxyresorufin-O-deethylase (EROD) activity was demonstrated, following treatment with 5 F 203. In contrast, in resistant AH(R100) cells, drug treatment did not affect CYPIAI and CYPIBI transcription and EROD activity. Furthermore, AHR(100) cells failed to produce either protein/DNA complexes on the xenobiotic responsive element (XRE) sequence of CYPIAI promoter (measured by electrophoretic mobility shift assay) or DNA adiducts. The data confirm that activation of the AhR signalling pathway is an important feature of the antitumour activity of 5F 203. (C) 2003 Cancer Research UK.

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