A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland

Purpose: We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)- negative breast cancer in vivo. Experimental Design: Incellculture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogenvinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen. For breast cancer prevention studies, mouse mammary tumor virus-neu mice were fed control diet or 4204 (20 mg/kg diet) for 50 weeks; for treatment, tumors at least 32 mm³ in size were allowed to form, and thenmice were fed control diet or 4204 (60mg/kg diet) for 4 weeks. Results: Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-α to induce the release of nitric oxide and interleukin 6 and the degradation of IKBα in RAW264.7 macrophage-like cells. In the A/J mouse model of lung cancer, 4204 significantly (P < 0.05) reduced the number and size of tumors on the surface of the lungs and reduced the total tumor volume per slide by 64% to 81% compared with the control group. Inmouse mammary tumor virus-neu mice, 4204 not only delayed the development of ER-negative mammary tumors in the prevention studies but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically. Conclusions: The combined anti-inflammatory and anticarcinogenic actions of 4204 suggest that it is a promising new rexinoid that should be considered for future clinical trials.