agn-194204 and Lung-Neoplasms

We tested members of two noncytotoxic classes of drugs, synthetic oleanane triterpenoids and rexinoids, both as individual agents and in combination, for the prevention and treatment of carcinogenesis in a highly relevant animal model of lung cancer. Lung adenocarcinomas were induced in A/J mice by injection of the carcinogen vinyl carbamate. Mice were fed drugs in diet, beginning 1 week after the carcinogen challenge for prevention or 8 weeks later for treatment. The number, size, and severity of tumors in the lungs were then evaluated. In the prevention studies, the triterpenoids CDDO-ethyl amide and CDDO-methyl ester reduced the average tumor burden (ATB) in the lungs 86% to 92%, respectively, compared with the controls, and the rexinoid LG100268 (268) reduced ATB by 50%. The combination of CDDO-ethyl amide and 268 reduced ATB by 93%. We show for the first time that these drugs also were highly effective for treatment of experimental lung cancer, and all triterpenoid and rexinoid combinations reduced ATB 85% to 87% compared with the control group. The triterpenoids also potently inhibited proliferation of VC1 mouse lung carcinoma cells and directly interacted with key regulatory proteins in these cells. In contrast, the rexinoids had little antiproliferative activity in VC1 cells but were potent inhibitors of the toll-like receptor pathway in macrophage-like cells. Triterpenoids and rexinoids are multifunctional, well-tolerated drugs that target different signaling pathways and are thus highly effective for prevention and treatment of experimental lung cancer.

Topics: Adenocarcinoma; Animals; Cell Proliferation; Fatty Acids, Unsaturated; Female; Ligands; Lung Neoplasms; Macrophages; Mice; Mice, Inbred A; Nicotinic Acids; Oleanolic Acid; Rats; Tetrahydronaphthalenes; Urethane

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.. In cell culture 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 carcinogen vinyl 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 then mice were fed control diet or 4204 (60 mg/kg diet) for 4 weeks.. Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-alpha to induce the release of nitric oxide and interleukin 6 and the degradation of IKBalpha 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. In mouse 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.. 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.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Carcinogens; Fatty Acids, Unsaturated; Humans; Interleukin-6; Lipopolysaccharides; Lung Neoplasms; Macrophages; Mammary Tumor Virus, Mouse; Mice; Models, Biological; Models, Chemical; Receptors, Estrogen; Receptors, Retinoic Acid; Tetrahydronaphthalenes