Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists.
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 7,12-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.
McDougal
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Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
Wilson
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Safe
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D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001572:Benzofurans / Q000627:therapeutic use*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C111836:8-methyl-1,3,8-trichlorodibenzofuran; C497398:ARNT protein, rat; D000970:Antineoplastic Agents; D001572:Benzofurans; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C054923:6-methyl-1,3,8-trichlorodibenzofuran; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015127:9,10-Dimethyl-1,2-benzanthracene; D019363:Cytochrome P-450 CYP1A1