Plate on an EG & G Berthold luminometer. In the year 2005. Molecular studies on the pharmacology of human colon cancer cell lines showed that seliciclib phosphorylation of retinoblastoma protein AC480 BMS-599626 were, rst In Cdk2 phosphorylation site and then at several locations. Seliciclib also causes an increase of Erk Erk 1 and 2 phosphorylation, although this can have little effect on the cell cycle. More importantly, by its inhibitory effect on Cdk7 and CDK9 inhibits seliciclib phosphorylation of RNA polymerase II and total RNA polymerase II activity t of the protein. This results in decreased expression of cyclins, including several cyclin D1, A, B1, which explained the observed effects on the global nnte phosphorylation of retinoblastoma and the general effects of the cell cycle of seliciclib in these models K Ren.
To go Ren, a decreasing proportion of cells in G1, decreased DNA synthesis in S phase and reported a moderate increase of cells in G2 / M. Other studies have shown that this drug also blocks the degradation of p53 by inhibiting BIX 02189 1094614-85-3 the expression of MDM2. Studies in the line of colorectal cancer Lovo show that the large S influence on these cells is the induction of cell death of all the chambers of the cell cycle. The antitumor efficacy of seliciclib in human tumor xenografts in Nacktm Mice was shown when 500 kg to 1 mg twice t Resembled or 200 kg to 1 mg three times t Administered possible. Pharmacokinetic pharmacodynamic relationships in the model of the c Lon HCT116 cancer xenograft been in humans and showed reduced phosphorylation of RB and decreased expression of cyclin D1 in the tumor tissue.
Seliciclib is active in LY294002 inhibiting the proliferation of cancer c Lon non-small cell lung cancer, breast cancer and prostate cancer xenografts people. In addition, induces apoptosis in B-cell chronic lymphocytic leukemia Chemistry caspasedependent prime Ren cells ex vivo, downregulation of antiapoptotic proteins XIAP and Mcl 1, and one obtains Hten expression of Bak and Bax cleavage. Furthermore, seliciclib shows anti-tumor activity of t in cultures of multiple myeloma cell lines, associated with induction of apoptosis with downregulation of Mcl 1 and interleukin-6 transcription and protein expression. Seliciclib has a pr Clinical pharmacokinetic profile is satisfactory and largely inactive metabolites gel deleted, With the carboxylate as the main metabolite in urine after administration of Mice and after incubation with liver microsomes.
Seliciclib green shown Ere AUC, elimination half-life of more and better intratumoral drug delivery, compared with the same 2,6,9-tri-substituted purine CDK inhibitors olomoucine and bohemine. Seliciclib is highly bound to plasma proteins Bound, principally Chlich to albumin. To better characterize the pharmacokinetics of this agent, a first in humans, a single oral dose study in healthy volunteers was conducted in 12 healthy volunteers, the administration 50-800 mg seliciclib. It showed that the substance is absorbed satisfactorily undergoes first-pass metabolism, has high protein binding and is rapidly and extensively distributed to tissues. The best was the main metabolite of carboxylate-binding protein with low, restricted Of spaces in the tissue distribution and renal clearance CONFIRMS. In view of these promising data seliciclib investigated in early clinical trials in patients