Follow up studies to research the application of PA 824 in changing drugs in e

more potent than 1 in several cell lines spreading in various tumor types, specially in ovarian tumor IGROV1 and breast tumor MDA MB 231 Lenalidomide cell lines. In the NCI hollow fiber assay, which measures the original growth inhibition efficiency on a selected panel of 12 tumor cell lines implanted in mice, 9 appeared to be stronger than 1 and 11, with highest total score of 66/96 ; and specifically an intraperitoneal score of 36/48 and a subcutaneous score of 30/48. In contrast, substance 11 shows a total score of 48/96. Depending on these data, we made a decision to evaluate further the toxicity of compound 9 and 11. In vivo accumulation of compounds 9 and 11 Compound 1 side effects are an important constraint for its used in antitumor therapy. Gene expression Thus, we determined experimentally the doses where compounds 9 and 11 could be safely dosed to mice upon both chronic and acute times and applying intravenous and intraperitoneal administration routes. When testing recurring doses via intravenous administration every two or three days for 8 cycles, the MTD for 1 is 0. 6 mg/Kg or 1,5mg/Kg, respectively, while for compound 9 is 12 mg/Kg or 24 mg/Kg, respectively. Ergo, it's demonstrably recognized that larger doses of compound 9 could be safely administered to rats in comparison to 1, especially in a repeated measure plan using intravenous injection. This is actually the preferred style of administration, since humans will be dosed intravenously, thus these data may be used as the kick off point for a comprehensive toxicology analysis system. Pharmacokinetic studies of compounds 1 and 9 Plasma levels of compounds 1 and 9 were quantified after intravenous injections at doses of 1 and 18 mg/kg, respectively. The attention of both substances in the bloodstream declined exponentially with time, following similar ARN-509 kinetics. Plasma levels of compound 9 were between 5 and 20 fold more than compound 1, reflecting the different amounts inserted initially. After 5 min plasma levels of compounds 1 and 9 were approximately 2,7 and 28 uM, respectively. After 30 min, the degree of compound 1 was about 0,2 uM and that of compound 9 of 1,7 uM. After 120 min, levels of both materials were below 0,1 uM. Based on these data, body approval does not appear responsible for the differences in accumulation detected for both substances.