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

• Published in: Breast cancer research and treatment Vol. 133; no. 1; pp. 137 - 144
• Main Authors: Goss, Paul E., Qi, Shangle, Hu, Haiqing, Gediya, Lalji K., Purushottamachar, Puranik, Godbole, Abhijit M., Njar, Vincent C. O.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.05.2012; Springer; Springer Nature B.V
• Subjects: Animal experimentation; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Bone Density - drug effects; Breast cancer; Cancer; Cancer research; Cancer therapies; Carcinoma; Carcinoma - drug therapy; Cell Size - drug effects; Cholesterol; Drug Screening Assays, Antitumor; Drug therapy; Estradiol - pharmacology; Estrogen; Female; Gynecology. Andrology. Obstetrics; Imidazoles - pharmacology; Imidazoles - therapeutic use; Lipid Metabolism - drug effects; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; Medical sciences; Medicine; Medicine & Public Health; Metabolites; Methylnitrosourea; Neoplasms, Hormone-Dependent - drug therapy; Oncology; Organ Size; Ovariectomy; Physiological aspects; Preclinical Study; Rats; Rats, Sprague-Dawley; Reproductive system; Rodents; Tretinoin; Tretinoin - analogs & derivatives; Tretinoin - blood; Tretinoin - pharmacology; Tretinoin - therapeutic use; Tumor Burden - drug effects; Tumors; Uterus - drug effects; Uterus - pathology; Vitamin A; VN/14-1; Breast cancer; Anti-tumor efficacy; Blockage of estrogenic stimulation on uterus; Retinoic acid metabolism blocking agent (RAMBA); Antineoplastic agent; Animal model; Breast disease; Rat; Treatment efficiency; Rodentia; Retinoid; Stimulation; Malignant tumor; Metabolism; Mammary gland diseases; Breast carcinoma; Vertebrata; Mammalia; Uterus; Female genital system; Pharmacokinetics; Retinoic acid; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1724-7

VN/14-1 [4-(±)-(1 H -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.