Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 35, No. 7, 972-983 (2007)
DOI: 10.1080/01926230701748271

Articles

Expression of Serine/Threonine Protein-Kinases and Related Factors in Normal Monkey and Human Retinas: The Mechanistic Understanding of a CDK2 Inhibitor Induced Retinal Toxicity

Grazia Saturno13, Manuela Pesenti1, Cristiano Cavazzoli1, Anna Rossi1,4, Anna M. Giusti1, Berthold Gierke2, Michael Pawlak2 and Miro Venturi1

1 Nerviano Medical Sciences (NMS), Accelera, v.le Pasteur 10, 20014 Nerviano MI, Italy
2 Natural and Medical Sciences Institute (NMI), at the University of Tuebingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany

Correspondence: Address correspondence to Grazia Saturno, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom; e-mail:grazia.saturno{at}icr.ac.uk

Protein-kinase inhibitors are among the most advanced compounds in development using the new drug discovery paradigm of developing small-molecule drugs against specific molecular targets in cancer. After treatment with a cyclin dependent kinase CDK2 inhibitor in monkey, histopathological analysis of the eye showed specific cellular damage in the photoreceptor layer. Since this CDK2 inhibitor showed activity also on other CDKs, in order to investigate the mechanism of toxicity of this compound, we isolated cones and rods from the retina of normal monkey and humans by Laser Capture Microdissection. Using Real-Time PCR we first measured the expression of cyclin dependent protein-kinases (CDK)1, 2, 4, 5, Glycogen synthase kinase 3β (GSK3β) and microtubule associated protein TAU. We additionally verified the presence of these proteins in monkey eye sections by immunohistochemistry and immunofluorescence analysis and afterwards quantified GSK3β, phospho-GSK3β and TAU by Reverse Phase Protein Microarrays. With this work we demonstrate how complementary gene expression and protein-based technologies constitute a powerful tool for the understanding of the molecular mechanism of a CDK2 inhibitor induced toxicity. Moreover, this investigative approach is helpful to better understand and characterize the mechanism of species-specific toxicities and further support a rational, molecular mechanism-based safety assessment in humans.

Key Words: kinase inhibitors • cyclin dependent kinases • retinal toxicity • LCM • protein array

Abbreviations: LCM, laser capture micro-dissection • CDK, cyclin-dependent protein-kinase • GSK β, glycogen synthase 3 beta • TAU, MAPT microtubule associated protein TAU • RPPM, reverse phase protein microarray • RT, reverse transcriptase


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