Elucidation Of Chemopreventive Effects Of Aerosolized Rapamycin And Dietary Myoinositol By Mechanistic Biomarkers In Mouse Lung

Abstract Rapamycin, an approved anti-rejection drug for patients undergoing organ transplantation, has shown antitumor activity in preclinical studies and clinical trials. However, concerns regarding the prevalence of pneumanitis in a small percentage of patients receiving the drug by injection have prompted us to test an alternative route of administration. Myoinositol is another agent that has shown excellent chemopreventive activity both in preclinical and clinical settings and is very well tolerated in humans. The objective of the current study is to investigate whether aerosolized rapamycin or myoinositol fortified diet can inhibit two key biomarkers of lung cancer, activated Akt and mTOR, in lungs and test the feasibility of two dosing regimens (continuous or intermittent dosing) on the same biomarker expression at multiple time points after the last dosing. Female A/J mice (8 wks old) were exposed to 5 different doses of myoinositol (0.01, 0.03, 0.1, 0.3 and 1% diet) or rapamycin by inhalation (0.001, 0.01, 0.1, 1 and 10 mg/kg) continuously for 5 days or every other day for 3 days in two separate experiments. After the last exposure, blood concentration (measured by GC-MS) and effect of each agent on phosphorylated-AKT (phospho-AKT at Thr308) and mTOR (phospho-S6 at Ser235/236) was assessed by immunohistochemistry. There was a good correlation between the dose-dependent increase in blood concentration of myoinositol (20 − 255 μM) or rapamycin (0.033-1.75 μM) and corresponding dose-dependent decrease in the expression of phospho-AKT (21-85%) and mTOR (10-69%) or phospho-AKT (54-60%) and mTOR (28-73%), respectively, in the lung compared to untreated controls. Interestingly, there was no significant difference between the two regimens in reducing the biomarker expression by either myoinositol or rapamycin and the expression levels continued to remain the same for up to 3 days after the last exposure or treatment. No toxicity was observed during or after the exposure and all animals showed normal body weight gain. In conclusion, this study showed that both rapamycin and myoinositol showed significant inhibition of phospho-AKT and phospho-mTOR expression from the basal level (AIN-76A diet control for myoinositol or air control for rapamycin) and that both these agents can be administered intermittently instead of continuously to observe similar effects. In addition, subsequent cancer prevention studies that are planned by administering agents at selected intervals should reduce or eliminate any associated toxicities from long term exposures (Supported by NCI #N01-CN-53301). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 941.