A g-Tocopherol-Rich Mixture of Tocopherols Inhibits Chemically-Induced Lung Tumorigenesis in A/J mice and Xenograft Tumor Growth

The present study investigated the effects of a preparation of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; intraperitoneal injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 μmole each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% γ-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30, 50 and 55%, respectively; P \u3c 0.05). For three groups of mice treated with NNK alone, the γ-TmT diet was given during the initiation stage (Week 0 to 3), post-initiation stage (Week 3 to 19) or the entire experimental period, and the tumor multiplicity was reduced by 17.8, 19.7 or 29.3%, respectively (P \u3c 0.05). γ-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36 or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary γ-TmT treatment significantly reduced tumor volume and tumor weight by 56 and 47%, respectively (P \u3c 0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of γ-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, γ-H2AX and nitrotyrosine in the tumors of the γ-TmT-treated mice. In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of δ-T \u3e γ-TmT \u3e γ-T, whereas α-T was not effective. These results demonstrate the inhibitory effect of γ-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of δ-T and γ-T