Rapamycin, an approved anti-rejection drug for organ transplantation, has shown antitumor activity in preclinical studies and clinical trials. However, concerns regarding the prevalence of pneumanitis in few patients receiving Rapamycin by injection have prompted us to pursue an alternative and hopefully less toxic route of administration. Previously, we have shown that there was a good correlation between the dose-dependent increase in blood levels of Rapamycin and corresponding dose-dependent decrease in the activity of two biomarkers (phospho-AKT and mTOR) in the mouse lung. We have also observed that there was no significant difference between continuous or intermittent dosing regimens in reducing p-AKT and mTOR activity by rapamycin as the activity levels continued to remain suppressed (60 % inhibition) for up to 3 days after the last exposure. The objective of the current study is to assess the maximum tolerated dose (MTD) of aerosolized rapamycin to select optimal doses for subsequent cancer prevention studies. Female A/J mice (8 wks old) were exposed to 3 different doses (0.1, 1 and 10 mg/kg — equivalent to 1.6, 15.8 and 158 mg/m3 of air, respectively) of rapamycin by Nose-Only inhalation for 1 hr/day, 3 days (every other day) per week for 6 weeks. No toxicity was observed during or after the exposure in all dose groups except that the animals exposed to 10 mg/kg of rapamycin showed relatively slow body weight gain compared to other dose groups. Hematology of whole blood showed no significant difference among different dosing groups. Lymphocyte subpopulation evaluated by flow cytometry in blood showed that rapamycin at all doses had no effect on the ratio of T-helper cells/cytotoxic T-cells (CD4+/CD8+). Also, rapamycin did not affect the number of T regulatory cells, which was assessed by measuring FoxP3+/CD3+ ratio (4-5% in all groups) in lungs processed for immunohistochemistry. Pathological evaluation of H&E stained lung sections did not find any dose-related abnormalities in all groups. In conclusion, this study showed that rapamycin did not cause any toxicity in mice exposed to rapamycin by inhalation for 6 weeks at the dose ranges tested, indicating that rapamycin via inhalation route could be a safe candidate as a chemopreventive agent against lung tumors (Supported by NCI #N01-CN-53301).

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A41.

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2010