The combination of triterpenoids and rexinoids for the prevention of experimental lung cancer

A114

Lung cancer will claim more than 160,000 lives in the United States in 2007. The 5 year survival rate in patients remains around 15% and has not changed in more than 30 years, so developing effective chemopreventive drugs is the only realistic approach to reduce the devastating mortality of this disease. We have previously shown that synthetic triterpenoids and rexinoids, as individual agents, significantly reduce the number, size and severity of lung tumors induced by the carcinogen vinyl carbamate in A/J mice. The methyl ester (CDDO-Me) of the triterpenoid CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) is currently in phase II clinical trials for the treatment of pancreatic cancer and melanoma, and a rexinoid is being considered for phase I trials in lung cancer. Because both classes of drugs target numerous biological pathways, including inflammation, angiogenesis, and apoptosis and because new experiments suggest that these drugs target different cell types, we decided to test the combination of these two classes of agents for the prevention of lung cancer. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg), once a week for two weeks. Starting one week after the last injection of carcinogen, the mice were fed the rexinoid LG100268 (268, 45 mg/kg diet), the triterpenoids CDDO-Me (40 mg/kg diet) or CDDO-EA (ethyl amide of CDDO, 400 mg/kg diet), or the combination of a triterpenoid and rexinoid for 16 weeks. CDDO-Me, CDDO-EA and 268 significantly (P < 0.05) reduced the average number of grossly visible tumors in the lungs from 14.7 in the control group (n = 22) to 7.5, 8.8 and 10.0 respectively (n = 12 per group). The average size of tumors on lung sections was also significantly reduced 34% by 268 and 76-83% with the triterpenoids. The total tumor volume per slide was 7.7 mm³ in the control group but only 3.9 mm³ in mice fed 268, 1.1 mm³ in mice fed CDDO-EA, and 0.6 mm³ in mice fed CDDO-Me (P < 0.05). Although the number and size of tumors was even lower in mice fed the combination of a triterpenoid and 268, these differences were not significant. However, the percentage of high grade tumors (histological and nuclear grade) were significantly lower in the mice fed the combination of CDDO-EA and 268 (2%) than the controls (61%) or the individual compounds (268, 43%; and CDDO-EA, 24%). Moreover, the combination diets were better tolerated than the diets containing individual drugs, as the average weight change for the mice on the combination diets over 16 weeks was indistinguishable from the controls. Similar results were seen in a separate experiment, in which diets were not started until 8 weeks after the final injection of carcinogen, and again the weight gains in the mice and the grade of the tumors were best in mice fed the combination of a triterpenoid and rexinoid. Additional combination studies will optimize the dose, timing and compound selection that will be most effective for the prevention of experimental lung cancer.
 >Supported by NIH grant R01 CA78814 and Reata Pharmaceuticals, Inc.