Figure 4a shows average tumor growth over time for the doxycycline treated animals. The data points represent days where at least four of the animals in a cohort had tumors meas ured. The day 26 average tumor volumes for the single agent Veliparib price doxycycline cohort and the doxycycline plus rapamycin treated animals were not significantly differ ent than the untreated group. The aver age tumor volume for doxycycline plus rapamycin was similar to the rapamycin cohort at day 42, and survival data for the doxycycline experiment was consistent with the tumor volume data. The median survival of the doxycycline plus rapamycin treated cohort was significantly increased compared to the untreated cohort but was similar to rapamycin treated animals. The median survival of the doxycycline cohort was not significantly different than the untreated cohort.

In summary, doxycycline Inhibitors,Modulators,Libraries was not effec tive as either a single agent or in combination with rapamycin in this preclinical model for TSC related tumors. Sorafenib, atorvastatin and doxycycline do not affect rapamycin levels in combination treatment cohorts Rapamycin is metabolized by CYP3A4 so rapamycin lev els can vary when there is exposure to other drugs that either induce or inhibit CYP3A4. To be sure there were no significant drug interaction issues in our studies, rapamycin levels were measured in tumors or whole blood 24 hours after the last dose in a subset of animals from our studies. Average tumor rapamycin lev els in the sorafenib plus rapamycin treated group and the rapamycin treated Inhibitors,Modulators,Libraries group were not statistically different.

Average blood rapamycin levels from nei ther the atorvastatin plus rapamycin group nor the doxycycline plus rapamycin group were statistically different from the average blood rapamycin level of the single agent rapamycin group. We have previously observed Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries higher 24 hour rapamycin levels in tumor tissue when compared with blood so the differences in tumor versus blood levels shown in Figure 5 are consistent with our prior results. Based on drug level testing, we conclude that sorafenib, atorvastatin, and dox ycycline did not significantly affect the metabolism of rapamycin in the preclinical studies reported here. Discussion In prior preclinical studies, we used two TSC2 tumor models to demonstrate that while both the rapamycin analog, CCI 779, and IFN g are effective in reducing tumor growth, rapamycin is more effective than CCI 779, and effective rapamycin doses are absorbed after topical administration. We also investigated the optimal timing of treatment using these models. We observed conflicting results regarding Inhibitors,Modulators,Libraries whether treatment with an mTOR inhibitor http://www.selleckchem.com/products/MLN8237.html plus IFN g is better than an mTOR inhib itor as a single agent.