title: Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus.
abstract: VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], a novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of all-trans-retinoic acid. The purpose of this study was to evaluate the anti-tumor effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, and peripheral organ effects on the uteri of immature ovariectomized (OVX) rats. In tumor burden experiments, after 56 days of administration of VN/14-1 5, 10, and 20 mg/kg/day, significant tumor reductions in mean tumor weight of 19.1, 34.4, and 44.3%, compared to tumors in control animals occurred. Cumulative tumor growth was also significantly slower in a dose-dependent manner in groups receiving 5, 10, and 20 mg/kg/day of VN/14-1 compared to growth rates in the control group. Tumor apoptosis was significant increases in animals treated with 5, 10, and 20 mg/kg/day of VN/14-1. In uterotrophic experiments, immature OVX rats given VN/14-1 significantly reduced uterine weight and blocked endometrial stimulation induced by unopposed β-estradiol (E2). In both rat models, adverse toxicities included weakness, anorexia, and reduction in body weight in the groups given the highest dose of 20 mg/kg/day. In summary, VN/14-1 inhibited tumor growth in the MNU-induced estrogen receptor (ER)-positive rat mammary tumor model, and antagonized the stimulatory effect of estrogens on the uterus. The studies suggest that VN/14-1 may be a useful novel therapy for ER-positive breast cancer.
authors.affiliation: Breast Cancer Research, Massachusetts General Hospital Cancer Center, Breast Cancer Disease Program, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02114, USA. pgoss@partners.org
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.forename: Shangle
authors.initials: S
authors.lastname: Qi
authors.forename: Haiqing
authors.initials: H
authors.lastname: Hu
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.forename: Abhijit M
authors.initials: AM
authors.lastname: Godbole
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D048429:Cell Size / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008770:Methylnitrosourea; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009929:Organ Size; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000473:pathology
chemical_list: C496751:4-(1H-imidazol-1-yl)retinoic acid; D000970:Antineoplastic Agents; D007093:Imidazoles; D004958:Estradiol; D014212:Tretinoin; D008770:Methylnitrosourea