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Prevention of Chemotherapy-Induced Alopecia in Rats by CDK Inhibitors
Stephen T. Davis,1*Bill G. Benson,2H. Neal Bramson,3Dennis E. Chapman,4Scott H. Dickerson,5Karen M. Dold,1Derek J. Eberwein,1Mark Edelstein,1Stephen V. Frye,5Robert T. Gampe Jr.,6Robert J. Griffin,4Philip A. Harris,5Anne M. Hassell,6William D. Holmes,7Robert N. Hunter,5Victoria B. Knick,1Karen Lackey,5Brett Lovejoy,6Michael J. Luzzio,5§Doris Murray,1Patricia Parker,1Warren J. Rocque,7Lisa Shewchuk,6James M. Veal,6Duncan H. Walker,1Lee F. Kuyper6
Most traditional cytotoxic anticancer agents ablate the rapidly
dividing epithelium of the hair follicle and induce alopecia(hair
loss). Inhibition of cyclin-dependent kinase 2 (CDK2), apositive
regulator of eukaryotic cell cycle progression, may representa
therapeutic strategy for prevention of chemotherapy-inducedalopecia
(CIA) by arresting the cell cycle and reducing the sensitivityof the
epithelium to many cell cycle-active antitumor agents.Potent
small-molecule inhibitors of CDK2 were developed usingstructure-based
methods. Topical application of these compoundsin a neonatal rat model
of CIA reduced hair loss at the site ofapplication in 33 to 50% of
the animals. Thus, inhibition of CDK2represents a potentially useful
approach for the prevention ofCIA in cancer patients.
1 Department of Cancer Biology,
2 Department of Discovery Genetics,
3 Department of Molecular Biochemistry,
4 Department of Biomet Research Support,
5 Department of Medicinal Chemistry,
6 Department of Structural Chemistry,
7 Department of Molecular Sciences, Glaxo Wellcome
Research and Development, 5 Moore Drive, Research Triangle Park, NC
27709, USA.
*
To whom correspondence should be addressed. E-mail:
std41085{at}glaxowellcome.com
Present address: Neurocrine Biosciences, 10555 Science
Center Drive, San Diego, CA 92121, USA.
Present address: Pennie & Edmonds LLP, 3300 Hillview
Avenue, Palo Alto, CA 94304, USA.
§
Present address: Pfizer Inc., Pfizer Central Research,
Eastern Point Road, Groton, CT 06340, USA.
Phosphorylation of Progesterone Receptor Serine 400 Mediates Ligand-Independent Transcriptional Activity in Response to Activation of Cyclin-Dependent Protein Kinase 2.
L. K. Pierson-Mullany and C. A. Lange (2004)
Mol. Cell. Biol.
24, 10542-10557
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Fas Signaling Is Involved in the Control of Hair Follicle Response to Chemotherapy.
A. A. Sharov, F. Siebenhaar, T. Y. Sharova, N. V. Botchkareva, B. A. Gilchrest, and V. A. Botchkarev (2004)
Cancer Res.
64, 6266-6270
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Expression of Cyclin E Renders Cyclin D-CDK4 Dispensable for Inactivation of the Retinoblastoma Tumor Suppressor Protein, Activation of E2F, and G1-S Phase Progression.
S. M. Keenan, N. H. Lents, and J. J. Baldassare (2004)
J. Biol. Chem.
279, 5387-5396
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Inhibition of Protein Kinase CK2 by Anthraquinone-related Compounds. A STRUCTURAL INSIGHT.
E. De Moliner, S. Moro, S. Sarno, G. Zagotto, G. Zanotti, L. A. Pinna, and R. Battistutta (2003)
J. Biol. Chem.
278, 1831-1836
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A Novel, Extraneuronal Role for Cyclin-dependent Protein Kinase 5 (CDK5). MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS.
T. Sandal, C. Stapnes, H. Kleivdal, L. Hedin, and S. O. Doskeland (2002)
J. Biol. Chem.
277, 20783-20793
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Effect of Adenovirus-Mediated Expression of Sonic Hedgehog Gene on Hair Regrowth in Mice With Chemotherapy-Induced Alopecia.
N. Sato, P. L. Leopold, and R. G. Crystal (2001)
J Natl Cancer Inst
93, 1858-1864
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Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells.
