This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Beliën, A. Articles by Arts, J. Search for Related Content PubMed PubMed Citation Articles by Beliën, A. Articles by Arts, J.

Research Articles: Therapeutics

Real-time gene expression analysis in human xenografts for evaluation of histone deacetylase inhibitors

¹ Oncology Discovery Research and Early Development, ² Global Information Solutions, and ³ Nonclinical Biostatistics, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium; and ⁴ HistoGenex, Edegem, Belgium

Requests for reprints: Janine Arts, Oncology Discovery Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Phone: 32-14-606325; Fax: 32-14-605403. E-mail: jarts{at}prdbe.jnj.com

Real-time analysis of gene expression in experimental tumor models represents a major tool to document disease biology and evaluate disease treatment. However, monitoring gene regulation in vivo still is an emerging field, and thus far it has not been linked to long-term tumor growth and disease outcome. In this report, we describe the development and validation of a fluorescence-based gene expression model driven by the promoter of the cyclin-dependent kinase inhibitor p21^waf1,cip1. The latter is a key regulator of tumor cell proliferation and a major determinant in the response to many anticancer agents such as histone deacetylase inhibitors. In response to histone deacetylase inhibitors, induction of fluorescence in A2780 ovarian tumors could be monitored in living mice in a noninvasive real-time manner using whole-body imaging. Single p.o. administration of the histone deacetylase inhibitor MS-275 significantly induces tumor fluorescence in a time- and dose-dependent manner, which accurately predicted long-term antitumoral efficacy in individual mice following extended treatment. These findings illustrate that this technology allows monitoring of the biological response induced by treatment with histone deacetylase inhibitors. In addition to providing experimental pharmacokinetic/pharmacodynamic markers for investigational drugs, this model provides insight into the kinetics of in vivo regulation of transcription, which plays a key role in causing and maintaining the uncontrolled proliferation of tumor tissue. [Mol Cancer Ther 2006;5(9):2317–24]

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/28/06; revised 6/16/06; accepted 6/29/06.