Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists

Andrew McDougal, Cody Wilson, Stephen Safe

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

The antitumorigenic activities of 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), 8-methyl-1,3,6-trichlorodibenzofuran (8-MCDF) and 6-cyclohexyl-1,3,8-trichlorodibenzofuran (6-CHDF) were investigated in the 3,12-dimethylbenz[a]anthracene (DMBA) rat mammary tumor model. At doses of 5, 10 or 25 mg/kg/week, both 6-MCDF and 8-MCDF significantly inhibited mammary tumor growth and at the 5 mg/kg/week dose > 50% growth inhibition was observed. In contrast, 6-CHDF was inactive at the 5 mg/kg/week dose and the structure-antitumorigenicity relationships (6-MCDF/8-MCDF > 6-CHDF) correlated with structure-antiestrogenicity (rat uterus) studies and the relative binding affinities of these compounds for the aryl hydrocarbon receptor (AhR). The antitumorigenic activity of 6-MCDF or 8-MCDF in the mammary was not accompanied by any significant changes in liver/body weight ratios, liver morphology or induction of hepatic CYP1A1-dependent activity which is one of the most sensitive indicators of exposure to AhR agonists. RT-PCR and Western blot analysis of mammary tumor mRNA and protein extracts, respectively, confirmed the presence of AhR suggesting that AhR-mediated signaling pathways are functional in rat mammary tumors. These results define a relatively non-toxic group of AhR agonists which exhibit potent antitumorigenic activity in the DMBA-induced rat mammary tumor model (< 1 mg/kg/day), and therefore represent a new class of indirect-acting antiestrogens which have potential for clinical treatment of mammary cancer.

Original languageEnglish (US)
Pages (from-to)53-63
Number of pages11
JournalCancer Letters
Volume120
Issue number1
DOIs
StatePublished - Nov 25 1997
Externally publishedYes

Keywords

  • Ah receptor agonist
  • Antitumorigenicity
  • Mammary

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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