Report

Quantifying the CDK inhibitor VMY-1-103’s activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI

Volume 11, Issue 20   October 15, 2012
Pages 3801 - 3809
http://dx.doi.org/10.4161/cc.21988
Keywords: CDK inhibitor, MR-spectroscopy, MRI, animal models, medulloblastoma, prostate, tandem mass spectrometry
Authors: Paul Sirajuddin, Sudeep Das, Lymor Ringer, Olga C. Rodriguez, Angiela Sivakumar, Yi-Chien Lee, Aykut Üren, Stanley T. Fricke, Brian Rood, Alpay Ozcan, Sean S. Wang, Sana Karam, Venkata Yenugonda, Patricia Salinas, Emanuel Petricoin III, Michael Pishvaian, Michael P. Lisanti, Yue Wang, Richard Schlegel, Bahram Moasser and Chris Albanese

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Abstract:
The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.

Received: July 22, 2012; Accepted: August 27, 2012; Published Online: September 14, 2012

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