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

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; Michael Pishvaian; Michael P. Lisanti; Yue Wang; Richard Schlegel; Bahram Moasser; Chris Albanese

doi:10.4161/cc.21988

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

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, Michael Pishvaian, Michael P. Lisanti, Yue Wang, Richard Schlegel, Bahram MoasserChris Albanese^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. 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 afected key metabolites in a mouse model of hedgehog-driven medulloblastoma.

Original language	English
Pages (from-to)	3801-3809
Number of pages	9
Journal	Cell Cycle
Volume	11
Issue number	20
DOIs	https://doi.org/10.4161/cc.21988
State	Published - 15 Oct 2012
Externally published	Yes

Keywords

Animal models
CDK inhibitor
MR-Spectroscopy
MRI
Medulloblastoma
Prostate
Tandem mass spectrometry

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10.4161/cc.21988

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Sirajuddin, P., Das, S., Ringer, L., Rodriguez, O. C., Sivakumar, A., Lee, Y. C., Üren, A., Fricke, S. T., Rood, B., Ozcan, A., Wang, S. S., Karam, S., Yenugonda, V., Salinas, P., Petricoin, E., Pishvaian, M., Lisanti, M. P., Wang, Y., Schlegel, R., ... Albanese, C. (2012). 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. Cell Cycle, 11(20), 3801-3809. https://doi.org/10.4161/cc.21988

@article{27a659c0fb1c469eb30cd9205f05a14f,

title = "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",

abstract = "The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. 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 afected key metabolites in a mouse model of hedgehog-driven medulloblastoma.",

keywords = "Animal models, CDK inhibitor, MR-Spectroscopy, MRI, Medulloblastoma, Prostate, Tandem mass spectrometry",

author = "Paul Sirajuddin and Sudeep Das and Lymor Ringer and Rodriguez, {Olga C.} and Angiela Sivakumar and Lee, {Yi Chien} and Aykut {\"U}ren and Fricke, {Stanley T.} and Brian Rood and Alpay Ozcan and Wang, {Sean S.} and Sana Karam and Venkata Yenugonda and Patricia Salinas and Emanuel Petricoin and Michael Pishvaian and Lisanti, {Michael P.} and Yue Wang and Richard Schlegel and Bahram Moasser and Chris Albanese",

note = "Funding Information: We would like to thank the Georgetown-Lombardi Preclinical Imaging Research laboratory for imaging the medulloblastoma mouse model and Dr. Gary Van Berkel for useful discussions on dansylation and mass spectrometry. The MRI was performed in the Lombardi Comprehensive Cancer Center{\textquoteright}s Preclinical Research Imaging Laboratory and the tissue sectioning and staining was performed in the Lombardi Comprehensive Cancer Center{\textquoteright}s Histology and Tissue Shared Resource. This work was supported by P30 CA51008 (Weiner), R01CA129003 (C.A.) and ABC2 (C.A.).",

year = "2012",

month = oct,

day = "15",

doi = "10.4161/cc.21988",

language = "English",

volume = "11",

pages = "3801--3809",

journal = "Cell Cycle",

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Sirajuddin, P, Das, S, Ringer, L, Rodriguez, OC, Sivakumar, A, Lee, YC, Üren, A, Fricke, ST, Rood, B, Ozcan, A, Wang, SS, Karam, S, Yenugonda, V, Salinas, P, Petricoin, E, Pishvaian, M, Lisanti, MP, Wang, Y, Schlegel, R, Moasser, B & Albanese, C 2012, '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', Cell Cycle, vol. 11, no. 20, pp. 3801-3809. https://doi.org/10.4161/cc.21988

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AU - Sirajuddin, Paul

AU - Das, Sudeep

AU - Ringer, Lymor

AU - Rodriguez, Olga C.

AU - Sivakumar, Angiela

AU - Lee, Yi Chien

AU - Üren, Aykut

AU - Fricke, Stanley T.

AU - Rood, Brian

AU - Ozcan, Alpay

AU - Wang, Sean S.

AU - Karam, Sana

AU - Yenugonda, Venkata

AU - Salinas, Patricia

AU - Petricoin, Emanuel

AU - Pishvaian, Michael

AU - Lisanti, Michael P.

AU - Wang, Yue

AU - Schlegel, Richard

AU - Moasser, Bahram

AU - Albanese, Chris

N1 - Funding Information: We would like to thank the Georgetown-Lombardi Preclinical Imaging Research laboratory for imaging the medulloblastoma mouse model and Dr. Gary Van Berkel for useful discussions on dansylation and mass spectrometry. The MRI was performed in the Lombardi Comprehensive Cancer Center’s Preclinical Research Imaging Laboratory and the tissue sectioning and staining was performed in the Lombardi Comprehensive Cancer Center’s Histology and Tissue Shared Resource. This work was supported by P30 CA51008 (Weiner), R01CA129003 (C.A.) and ABC2 (C.A.).

PY - 2012/10/15

Y1 - 2012/10/15

N2 - The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. 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 afected key metabolites in a mouse model of hedgehog-driven medulloblastoma.

AB - The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. 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 afected key metabolites in a mouse model of hedgehog-driven medulloblastoma.

KW - Animal models

KW - CDK inhibitor

KW - MR-Spectroscopy

KW - MRI

KW - Medulloblastoma

KW - Prostate

KW - Tandem mass spectrometry

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DO - 10.4161/cc.21988

M3 - Article

C2 - 22983062

AN - SCOPUS:84868021546

SN - 1538-4101

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EP - 3809

JO - Cell Cycle

JF - Cell Cycle

IS - 20

ER -

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

Abstract

Keywords

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