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: Paul E Goss, Shangle Qi, Haiqing Hu, Lalji K Gediya, Puranik Purushottamachar, Abhijit M Godbole, Vincent C O Njar
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 133 Issue 1 Pg. 137-44 (May 2012) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 21842418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 4-(1H-imidazol-1-yl)retinoic acid
• Antineoplastic Agents
• Imidazoles
• Estradiol
• Tretinoin
• Methylnitrosourea

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Bone Density (drug effects)
• Carcinoma (drug therapy)
• Cell Size (drug effects)
• Drug Screening Assays, Antitumor
• Estradiol (pharmacology)
• Female
• Imidazoles (pharmacology, therapeutic use)
• Lipid Metabolism (drug effects)
• Mammary Neoplasms, Experimental (drug therapy)
• Methylnitrosourea
• Neoplasms, Hormone-Dependent (drug therapy)
• Organ Size
• Ovariectomy
• Rats
• Rats, Sprague-Dawley
• Tretinoin (analogs & derivatives, blood, pharmacology, therapeutic use)
• Tumor Burden (drug effects)
• Uterus (drug effects, pathology)