Inhibition of carcinogen-induced rat mammary tumor growth and other estrogen-dependent responses by symmetrical dihalo-substituted analogs of diindolylmethane.
90%) by the haloDIMs at concentrations of 5 or 10 microM, and only 4, 4'-dichloroDIM alone increased cell proliferation. With the exception of 5,5'-difluoroDIM, the remaining compounds also inhibited E2-induced growth of MCF-7 human breast cancer cells. DihaloDIMs (100 mg/kg/dayx3) were not estrogenic in the immature female B6C3F1 mouse uterus; however, in animals co-treated with E2 (0.02 microg/mouse), 5,5'-dichloro- and 6,6'-dichloroDIM inhibited uterine progesterone receptor (PR) binding and uterine peroxidase activity, whereas 5,5'-dichloro- and 5,5'-dichloro-2,2'-dimethylDIM inhibited only the latter response. The antitumorigenic activities of the dihaloDIMs were determined by their inhibition of carcinogen-induced mammary tumor growth in female Sprague-Dawley rats. 4,4'-Dichloro-, 5,5'-dibromo- and 6,6'-dichloroDIM, significantly inhibited mammary tumor 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 three compounds were more active than DIM in the same in vivo assay.
McDougal
A
A
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
Sethi Gupta
M
M
Ramamoorthy
K
K
Sun
G
G
Safe
S H
SH
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006219:Halogens / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D004965:Estrogen Antagonists; D006219:Halogens; D007211:Indoles; D011980:Receptors, Progesterone; D004958:Estradiol; D009195:Peroxidase; C016392:3,3'-diindolylmethane