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Research Articles: Therapeutics

Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies

¹ CuraGen Corporation, Branford, Connecticut and ² TopoTarget, Copenhagen, Denmark

Requests for reprints: Michael Jeffers, CuraGen Corporation, 322 East Main Street, Branford, CT 06405. Phone: 203-871-4356; Fax: 203-315-3301. E-mail: mjeffers{at}curagen.com

Histone deacetylase inhibitors represent a promising new class of anticancer agents. In the current investigation, we examined the activity of PXD101, a potent histone deacetylase inhibitor, used alone or in combination with clinically relevant chemotherapeutics (docetaxel, paclitaxel, and carboplatin), in preclinical in vitro and in vivo models of ovarian cancer. In vitro activity was examined in ovarian cancer and multidrug-resistant cell lines grown in monolayer culture, and in primary clinical ovarian cancer specimens grown in three-dimensional organoid culture. PXD101 was found to inhibit in vitro cancer cell growth at sub- to low micromolar IC₅₀ potency, exhibited synergistic activity when used in combination with relevant chemotherapeutics, and effectively inhibited the growth of multidrug-resistant cells. In vivo, PXD101 displayed single-agent antitumor activity on human A2780 ovarian cancer s.c. xenografts which was enhanced via combination therapy with carboplatin. In support of these findings, PXD101 was shown to increase the acetylation of -tubulin induced by docetaxel and the phosphorylation of H2AX induced by carboplatin. Taken together, these results support the clinical evaluation of PXD101 used alone or in combination therapy for the treatment of ovarian cancer. [Mol Cancer Ther 2006;5(8):2086–95]

³ M. Sehested and H.S. Lichenstein, unpublished data.

⁴ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/28/06; revised 5/ 2/06; accepted 6/15/06.

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