B141

Lung cancer has been the leading cause of death among all the malignancies for decades with relatively small improvement in its treatment. Preventing the development of lung cancer, therefore, would be an alternative strategy to help fight this disease. As smoking is the major cause of lung cancer, smokers and ex-smokers would be the population to benefit the most from an effective lung chemopreventive agent.
 >Based on epidemiological information, kava - a traditional beverage in the South Pacific Island region, is potentially chemopreventive against lung tumorigenesis. Its chemopreventive effect, however, has never been evaluated. In addition, the potential hepatotoxicity of kava presents a major barrier to its chemopreventive application. In this study, we evaluated whether oral kava could prevent NNK- and B[a]P-induced lung tumorigenesis in A/J mouse and whether such kava treatment would induce hepatotoxicity.
 >Lung tumorigenesis was induced in A/J mouse with weekly gavage administration of 2 µmol NNK and 2 µmol B[a]P for eight consecutive weeks. To evaluate the potential chemopreventive activity, kava was administered orally as a supplement to standard diet at the dose of 10 mg/g diet (this specific dose was chosen based on an in-house pilot toxicity study and a similar toxicity study performed by National Toxicology Programs). Such diet was administered to A/J mice (20 mice per group) through three courses - either administered only during the carcinogen-treatment (eight weeks); or administration started after the last carcinogen treatment (22 weeks); or administered throughout the whole experimental period (30 weeks). It was found that the 30-week kava treatment had statistically significant lower lung tumor multiplicities (i.e., mean number of tumors/mouse) than NNK + B[a]P-treated mice [12.8 tumors/mouse in the NNK + B[a]P group versus 5.65 tumors/mouse in the NNK + B[a]P + Kava group; difference, 7.15 tumors/mouse; 95% CI, 3.9 to 10.6 tumors/mouse; P < 0.0001], corresponding to a 55.9% of tumor reduction. The 8-week treatment concurrent with carcinogen treatment also reduced lung tumor multiplicities [12.8 tumors/mouse in the NNK + B[a]P group versus 6.79 tumors/mouse in the NNK + B[a]P + Kava group; difference, 6.01 tumors/mouse; 95% CI, 2.4 to 9.7 tumors/mouse; P = 0.0018], corresponding to a 47.1% of tumor reduction. More excitingly, post-carcinogen treatment reduced the tumor multiplicity significantly as well [12.8 tumors/mouse in the NNK + B[a]P group versus 6.59 tumors/mouse in the NNK + B[a]P + Kava group; difference, 6.21 tumors/mouse; 95% CI, 2.6 to 9.9 tumors/mouse; P = 0.0014], corresponding to a 48.7% of tumor reduction. These results demonstrated the chemopreventive potential of kava against lung tumorigenesis, especially its potential application to ex-smokers for chemoprevention.
 >Under these treatments, kava induced no detectable hepatotoxicity as characterized by the following parameters - body weight, liver weight, ALT, AST, GGT enzymatic activities, and liver pathology.
 >Taken together, this pilot study demonstrated the potential of kava as an effective and safe chemopreventive agent against lung tumorigenesis.

Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA