Inhibition of carcinogen-induced rat mammary tumor growth and other estrogen-dependent responses by symmetrical dihalo-substituted analogs of diindolylmethane

This study investigates the antiestrogenic/estrogenic and antitumorigenic a ctivities of the following diindolylmethane (DIM) derivatives: 4,4'-dichlor o-, 5,5'-dichloro-, 6,6'-dichloro-, 5,5'-dibromo-, 5,5'-difluoro- and 5,5'- dichloro-2,2'-dimethylDIM. E2-induced proliferation of T47D breast cancer c ells was significantly inhibited (>90%) by the haloDIMs at concentrations o f 5 or 10 muM, and only 4,4'-dichloroDIM alone increased cell proliferation . With the exception of 5,5'-difluoroDIM, the remaining compounds also inhi bited E2-induced growth of MCF-7 human breast cancer cells. DihaloDIMs (100 mg/kg/ day x 3) were not estrogenic in the immature female B6C3F1 mouse ut erus; however, in animals co-treated with E2 (0.02 mug/mouse), 5,5'-dichlor o- and 6,6'-dichloroDIM inhibited uterine progesterone receptor (PR) bindin g and uterine peroxidase activity, whereas 5,5'-dichloro- and 5,5'-dichloro -2,2'-dimethylDIM inhibited only the latter response. The antitumorigenic a ctivities of the dihaloDIMs were determined by their inhibition of carcinog en-induced mammary tumor growth in female Sprague-Dawley rats. 4,4'-Dichlor o-, 5,5'-dibromo- and 6,6'-dichloroDIM, significantly inhibited mammary tum or growth at doses of 1 mg/kg every second day, and no significant changes in organ weights or liver and kidney histopathology were observed. These th ree compounds were more active than DIM in the same in vivo assay. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.