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@article{Raynaud:2005:10.1158/1078-0432.CCR-04-2264,
author = {Raynaud, FI and Whittaker, SR and Fischer, PM and McClue, S and Walton, MI and Barrie, SE and Garrett, MD and Rogers, P and Clarke, SJ and Kelland, LR and Valenti, M and Brunton, L and Eccles, S and Lane, DP and Workman, P},
doi = {10.1158/1078-0432.CCR-04-2264},
journal = {Clin Cancer Res},
pages = {4875--4887},
title = {In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202.},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-04-2264},
volume = {11},
year = {2005}
}

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TY  - JOUR
AB  - PURPOSE: To investigate pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine, and CYC202 (R-roscovitine; seliciclib) in the HCT116 human colon carcinoma model. EXPERIMENTAL DESIGN: The in vitro activity of the agents was determined in a human tumor panel using the sulforhodamine B assay. The concentration and time dependence was established in HCT116 cells. Molecular biomarkers, including RB phosphorylation and cyclin expression, were assessed by Western blotting. Pharmacokinetic properties were characterized in mice following analysis by liquid chromatography-tandem mass spectrometry. Based on these studies, a dosing regimen was developed for CYC202 that allowed therapeutic exposures in the HCT116 tumor xenograft. RESULTS: The antitumor potency of the agents in vitro was in the order olomoucine (IC50, 56 micromol/L) < bohemine (IC50, 27 micromol/L) < CYC202 (IC50, 15 micromol/L), corresponding to their activities as cyclin-dependent kinase inhibitors. Antitumor activity increased with exposure time up to 16 hours. The agents caused inhibition of RB and RNA polymerase II phosphorylation and depletion of cyclins. They exhibited relatively rapid clearance following administration to mice. CYC202 displayed the slowest clearance from plasma and the highest tumor uptake, with oral bioavailability of 86%. Oral dosing of CYC202 gave active concentrations in the tumor, modulation of pharmacodynamic markers, and inhibition of tumor growth. CONCLUSIONS: CYC202 showed therapeutic activity on human cancer cell lines in vitro and on xenografts. Pharmacodynamic markers are altered in vitro and in vivo, consistent with the inhibition of cyclin-dependent kinases. Such markers may be potentially useful in the clinical development of CYC202 and other cyclin-dependent kinase inhibitors.
AU  - Raynaud,FI
AU  - Whittaker,SR
AU  - Fischer,PM
AU  - McClue,S
AU  - Walton,MI
AU  - Barrie,SE
AU  - Garrett,MD
AU  - Rogers,P
AU  - Clarke,SJ
AU  - Kelland,LR
AU  - Valenti,M
AU  - Brunton,L
AU  - Eccles,S
AU  - Lane,DP
AU  - Workman,P
DO  - 10.1158/1078-0432.CCR-04-2264
EP  - 4887
PY  - 2005///
SN  - 1078-0432
SP  - 4875
TI  - In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202.
T2  - Clin Cancer Res
UR  - http://dx.doi.org/10.1158/1078-0432.CCR-04-2264
UR  - https://www.ncbi.nlm.nih.gov/pubmed/16000586
VL  - 11
ER  -

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