Abstract
BackgroundLiarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats.Methods(1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 μg/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured.ResultsThe tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen.ConclusionLiarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile.
Highlights
Liarozole fumarate is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA)
Liarozole's antitumor effects on estrogen receptor (ER) positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer
Prolonged treatment with retinoids is hampered by the induction of retinoid acid (RA) metabolism resulting in a rapid fall in intracellular retinoid levels possibly accounting for their lack of clinical efficacy
Summary
Liarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Retinoids (compounds including vitamin A and its synthetic and naturally occurring analogs) are key molecules in cellular proliferation and differentiation [8]. Prolonged treatment with retinoids is hampered by the induction of retinoid acid (RA) metabolism resulting in a rapid fall in intracellular retinoid levels possibly accounting for their lack of clinical efficacy. This has led to the synthesis of a new class of agents called retinoic acid metabolism blocking agents (RAMBAs), which inhibit the P450-mediated catabolism of RA, leading to sustained increases in intracellular tissue and plasma retinoid levels [17,18,19,20,21,22,23]
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