Seventy three percent of patients randomized to placebo cro

Results Effect of RAD001 alone or in combination with endocrine therapy on cell growth To enable the study of an AI in combination KU-0063794 938440-64-3 with evero limus, we used our MCF 7 and BT474 cells that had been genetically engineered to express aromatase and pro vided 10 nM androstenedione as growth support. Our long term estrogen deprived MCF7 cell line was used to model acquired resistance to an AI. These cells show increased expression of HER2 but do not express aromatase, RAD001 alone caused a concentration dependent decrease in proliferation in all the cell lines tested, The median inhibitory concentration for RAD001 was between 0. 25 and 0. 5 nM for MCF7 AROM1 in the pre sence of androstenedione and 0. 5 nM for BT474 AROM3 in the presence of androstenedione. The LTED cell line showed the great est sensitivity, with an IC50 of 0.<br><br> 2 nM in the absence of exogenous E2 versus 0. 6 nM RAD001 in the presence of E2, The effect of doubling concentrations of RAD001 in combination with letrozole or 4 OH tamoxifen was assessed; the concentrations of each of the endocrine agents were close to their mean plasma levels obtained at the recommended doses of 2. 5 mg day letro zole or 20 mg day tamoxifen. It should Lenalidomide 404950-80-7 be noted that although 4 OH tamoxifen is a major active metabolite of tamoxifen, other metabolites may contribute to the clinical activity of this agent. Both letrozole and 4 OH tamoxifen alone decreased proliferation compared with androstene dione in MCF7 AROM1 cells, and a modest extra benefit was noted when added to RAD001, BT474 AROM3 cells showed sensitivity to letrozole alone but were resistant to 4 OH tamoxifen, Of note, the combination of letrozole or 4 OH tamoxifen with doubling concentrations of RAD001 showed greater efficacy than RAD001 alone.<br><br> The LTED cells were used to model the cessation of AI at relapse by the addition of 0. 01 nM E2. RAD001 was marginally more effective in the absence of added E2 versus IC50 0. 63 nM in the presence of E2, Similar to the BT474 AROM3 cells, addition of 4 OH LY2603618 分子量 tamoxifen improved the efficacy of RAD001, We subsequently conducted formal assessment of the interaction between letrozole and 4 OH tamoxifen with RAD001. Calcusyn software was used to establish the IC50 dose of 4 OH tamoxifen, letrozole, and RAD001 for each of the cell lines. These were then combined in equipotent fixed dose ratios.<br><br> The antiproliferative effect of the drugs at their IC50 values alone and in combination is shown in Figure 2A through 2E. The tables are derived from equi potent doses of the drugs giving 50%, 75%, and 90% growth inhibition. Although from our initial analyses, enhancement of the antiproliferative effect of RAD001 was seen when combined with the endocrine agents in all cir cumstances, formal estimates showed a variety of interactions.