Chemopreventive effects of α-tocopheryl succinate on lung carcinogenesis: Aerosolized lung delivery and role in combination chemotherapy.

B94

Lung cancer is the leading cause of cancer deaths in the US and other developed countries, and there remains a tremendous need for improvements in its prevention, including novel combined chemotherapies. Tocopheryl succinate (but not vitamin E) has been shown to kill lung cancer cells and many other kinds of cancer cells, but not normal cells. When taken orally, tocopheryl succinate (αTS) is hydrolyzed to tocopherol (αT, Vitamin E) and succinic acid, and the beneficial effects of αTS are lost. We developed a system for generating aerosols of lipophilic drugs using supercritical fluid carbon dioxide, and demonstrated that it is effective for pulmonary delivery of substances such as αTS. Using this drug delivery system we generated respirable, micron-sized particles of αTS. In this pilot project, we administered αTS directly to the lungs as an inhaled aerosol to determine the chemopreventive effects of αTS on lung tumorigenesis using the A/J mouse model. This model has been used extensively to study lung cancer chemoprevention strategies. At 9-10 weeks old the mice received a single intraperitoneal injection of one of the carcinogens 3, 4-benzopyrene (BaP, 100 mg/kg in tricaprylin vehicle); untreated cage mates were used as controls. Following carcinogen treatment, αTS group were treated with aerosol (30 min inhalation of 30 mg/ml αTS) twice weekly for twelve weeks. All mice were sacrificed sixteen weeks after carcinogen injection. All mice in both carcinogen treated groups developed adenomas. No aerosol treatment increased tumor multiplicity to 4.250 ± 0.94 (N=4). Aerosolized αTS, however was associated with a significant ( P = 0.016) chemopreventive effect by decreasing tumor multiplicity to 1.333 ± 0.49 (N=6) with one of the six mice exhibiting no tumor formation at all. We further examined potential synergistic anticancer effects of αTS when combined with commonly used Taxanes (Paclitaxel and Docetaxel) and Platinums (Cisplatin and Carboplatin) in A549 human non-small cell lung cancer cell line. Using MTT assay, IC50 was determined for each drug. Dose-Response effect of each of these drugs was determined alone and in combination with IC50 of VES (40μM). Median-Effect analysis indicated that the interaction of each of the drugs with αTS resulted in a synergistic effect with combination indexes below 1. These results suggest a possible chemopreventive role of αTS in reducing the development of lung tumors in high risk population. Further ongoing studies will fully characterize the role of this compound in combination and targeted chemotherapy. [Supported in part by grants from: ACS-PF-06-005-01-CCE, NIH-NCI-CA112652, Cancer Research and Prevention Foundation]