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Immunohistochemical Analysis of Acetylation, Proliferation, Mitosis, and Apoptosis in Tumor Xenografts Following Administration of a Histone Deacetylase Inhibitor—A Pilot Study
1 School of Biosciences, Birmingham University, Edgbaston, Birmingham, United Kingdom Correspondence: Address correspondence to: Tijana Mitiæ, Centre for Cardiovascular Science, Queen’s Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom; e-mail:t.mitic{at}sms.ed.ac.uk Histone acetyltransferases and histone deacetylases are protein-modifying enzymes involved in addition and removal of acetyl groups on histone proteins, respectively. These molecules play a pivotal role in cellular functions such as chromosome remodelling, gene transcription and cell proliferation. Histone deacetylase inhibitors (HDIs) have been shown to cause cell cycle arrest, cellular differentiation and inhibition of cell proliferation in tumor cells in vitro and in vivo. Their potential use for cancer therapy is currently under evaluation in clinical trials. A pilot study was performed to immunohistochemically evaluate the effects of a HDI, "Compound 1," on acetylation, proliferation, mitosis, and apoptosis in tumor xenografts (Calu-6, SW 620, Colo 205, and LoVo) in nude mice, at 6, 24, and 48 hours, following a single oral dose. Qualitative immunohistochemistry and computer-assisted image analysis demonstrated an increase in acetylation in all xenografts. Immunohistochemical analysis of acetylation in skin showed increased acetylation at 6 hours after HDI administration. In addition, image analysis showed a decrease in mitosis and an increase in metaphase mitotic figures in the SW 620 xenograft. These two findings were consistent with a G1/S cell cycle phase arrest. Increased apoptosis of SW 620 and LoVo xenografts was also observed following treatment.
Key Words: Acetylation • proliferation • apoptosis • xenografts • animal model • pharmacodynamics Abbreviations: IHC, immunohistochemistry • HDAC, histone deacetylase • HDI, histone deacetylase inhibitor • HAT, histone acetyltransferase • AcH3, acetylated histone H3 • PH3, phosphohistone H3 • Calu-6, human epithelial-like anaplastic carcinoma (probably lung) • Colo 205, SW 620 and LoVo, epithelial-like human colon adenocarcinoma • EACC, European Collection of Cell Cultures • ATCC, American Type Culture Collection • PD, pharmacodynamic • H&E, hematoxylin and eosin • DAB, diaminobenzadine • IMS, industrial methylated spirits • HLS, hue, luminosity, saturation
Toxicologic Pathology, Vol. 33, No. 7,
792-799 (2005) This article has been cited by other articles:
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