Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model.

Abstract

Abstract Abstract #2133 Background: All-trans-retinoic acid (ATRA) and other retinoids play key roles in prevention and therapy of many proliferative diseases including cancers. VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], which is a new generation novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of ATRA. The inhibitory effects of VN/14-1 on the growth of human breast cancer cells and human breast tumors in the nude mouse model have been previously demonstrated. The purpose of this study was to evaluate the effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in immature ovariectomized (OVX) rats.
 Methods: (1) VN/14-1 (5, 10, and 20 mg/kg/d) was given by oral gavage to grouped female Sprague Dawley (SD) rats bearing MNU-induced mammary carcinoma for 8 weeks, after which tumor weight and volume, as well as histology were measured. (2) VN/14-1 (10 and 20 mg/kg/d) and b-estradiol (10 mg/kg/d) were given alone or in combination, by oral gavage (VN/14-1) and subcutaneous injection (b-estradiol), to immature OVX SD rats for 3 days, after which uterine weight and histology were measured.
 Results: (1) At the end of the treatment period, the administration of 5, 10 and 20 mg/kg/d VN/14-1 caused significant reductions of 19.1, 34.4 and 44.3%, respectively, in mean tumor weight compared with the control animals (all p < 0.05). The cumulative tumor growth was also significantly slower in groups receiving 5, 10 and 20 mg/kg/d compared to the control group in a dose-dependent manner. (2) Immature OVX rats given VN/14-1 at doses of 10 and 20 mg/kg, had reduction in uterine wet weight of up to 56% compared to OVX controls (P < 0.001). OVX rats given VN/14-1 of 10 and 20 mg/kg in combination with β-estradiol had reduction in uterine wet weight of up to 58% compared to the OVX rats given β-estradiol alone (P < 0.001). The adverse toxic effects such as fatigue and anorexia were occurred in the groups at high dose of 20 mg/kg.
 Conclusions: RAMBA VN/14-1 was able to inhibit the growth of tumors in the MNU-induced ER positive rat mammary tumor model and antagonized the stimulatory effect of β-estradiol on the uterus. The studies suggest VN/14-1 might be an effective novel therapy for ER positive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2133.