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

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 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.

• Authors: A McDougal, C Wilson, S Safe
• Journal: Cancer letters (Cancer Lett) Vol. 120 Issue 1 Pg. 53-63 (Nov 25 1997) ISSN: 0304-3835 [Print] Ireland
• PMID: 9570386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 8-methyl-1,3,8-trichlorodibenzofuran
• ARNT protein, rat
• Antineoplastic Agents
• Benzofurans
• DNA-Binding Proteins
• Estrogen Antagonists
• Receptors, Aryl Hydrocarbon
• Transcription Factors
• 6-methyl-1,3,8-trichlorodibenzofuran
• Aryl Hydrocarbon Receptor Nuclear Translocator
• 9,10-Dimethyl-1,2-benzanthracene
• Cytochrome P-450 CYP1A1

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Antineoplastic Agents (therapeutic use)
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Benzofurans (therapeutic use)
• Cytochrome P-450 CYP1A1 (genetics)
• DNA-Binding Proteins
• Estrogen Antagonists (therapeutic use)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Mammary Neoplasms, Experimental (chemically induced, pathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Aryl Hydrocarbon (agonists, genetics)
• Transcription Factors (genetics)