| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
Department of Cancer Medicine, Cancer Research Campaign Laboratories, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London W12 0NN [D. M. V., S. A., P. E. P., N. M., R. C. C.], and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London SW3 6LY [K. I., I. A.], United Kingdom
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
Experimental Design and Results: TSA inhibited proliferation of eight breast carcinoma cell lines with mean ± SD IC50 of 124.4 ± 120.4 nM (range, 26.4–308.1 nM). HDAC inhibitory activity of TSA was similar in all cell lines with mean ± SD IC50 of 2.4 ± 0.5 nM (range, 1.5–2.9 nM), and TSA treatment resulted in pronounced histone H4 hyperacetylation. In randomized controlled efficacy studies using the N-methyl-N-nitrosourea carcinogen-induced rat mammary carcinoma model, TSA had pronounced antitumor activity in vivo when administered to 16 animals at a dose of 500 µg/kg by s.c. injection daily for 4 weeks compared with 14 control animals. Furthermore, TSA did not cause any measurable toxicity in doses of up to 5 mg/kg by s.c. injection. Forty-one tumors from 26 animals were examined by histology. Six tumors from 3 rats treated with TSA and 14 tumors from 9 control animals were adenocarcinomas. In contrast, 19 tumors from 12 TSA-treated rats had a benign phenotype, either fibroadenoma or tubular adenoma, suggesting that the antitumor activity of TSA may be attributable to induction of differentiation. Two control rats each had tumors with benign histology.
Conclusions: The present studies confirm the potent dose-dependent antitumor activity of TSA against breast cancer in vitro and in vivo, strongly supporting HDAC as a molecular target for anticancer therapy in breast cancer.
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
Cell Proliferation Assay.
Stock cultures of breast cancer cell lines MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, and SK-BR-3 (American Type Culture Collection, Rockville, MD) were grown in DMEM containing 10% (v/v) FCS, 2 mM L-glutamine, 100 units/ml penicillin, and 100 µg/ml streptomycin at 37°C in 5% CO2 humidified atmosphere. Cells were counted in a hemocytometer after detachment using 0.25% (w/v) trypsin in Dulbecco’s PBS without Ca2+ or Mg2+ (DPBS; Sigma-Aldrich) containing 0.02% (w/v) EDTA. Viability was determined by trypan blue exclusion. For each cell line, cells were seeded in 96-well microtiter plates at optimal densities determined in prior experiments to ensure exponential growth for the duration of the assay. After a 24-h preincubation, growth medium was replaced with experimental medium containing TSA at final concentrations ranging from 10-12 M to 10-5 M in log dilutions and 0.1% (v/v) ethanol, or growth medium containing 0.1% (v/v) ethanol as a vehicle control. After 96 h incubation, cell proliferation was estimated using the sulforhodamine B colorimetric assay (11)
, and the results are expressed as the mean ± SD for six replicates as a percentage of vehicle control (taken as 100%).
Immunodetection of Acetylated Histone H4.
Immunodetection of acetylated histone H4 in cell lines by Western blotting was performed as described (10
, 12)
, with the following modifications. Each cell line (
1 x 105 cells) was treated with 2 µM TSA in 0.1% ethanol or with 0.1% ethanol as vehicle control for 24 h at 37°C. Cells were lysed directly in 200 µl of boiling Laemmli sample buffer containing 10% (v/v) 2-mercaptoethanol. Protein concentration of each sample was determined using the Bio-Rad (Bradford) Protein Assay kit (Bio-Rad Laboratories, Ltd., Hertfordshire, United Kingdom). Each sample (20 µg protein) was then separated by 4–12% gradient SDS-PAGE (NuPAGE; Invitrogen, Groningen, the Netherlands). Proteins were transferred by electroblotting onto nitrocellulose membrane (Immobilon-NC HAHY; Millipore, Hertfordshire, United Kingdom), and acetylated histone H4 was detected with a rabbit polyclonal antihuman acetylated H4 antibody (Upstate Biotechnology, Lake Placid, NY) diluted 1:1000 in 3% nonfat dried milk powder in 150 mM NaCl, 10 mM Tris (pH 8.0). A goat antirabbit IgG F(ab')2 secondary antibody-alkaline phosphatase conjugate (Sigma-Aldrich) was visualized using 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium color substrate.
Immunoprecipitation of Human Estrogen Receptor 
and Western Blot Analysis.
MCF-7 cells (2.5 x 106) at 70–80% confluence in 15-cm plates were treated with 0.5 µM TSA in 0.1% ethanol or 0.1% ethanol as vehicle control for 24 h at 37°C. After washing with chilled DPBS, cells were harvested in DPBS, pelleted by centrifugation (1000 x g for 5 min at 4°C), and resuspended in 100 µl of high salt buffer [400 mM KCl, 20 mM Tris (pH 7.4), 2 mM DTT, and 20% (v/v) glycerol] containing a freshly added mixture of protease inhibitors (1 mM PMSF and 0.5 µg/ml each of leupeptin, pepstatin A, chymostatin, antitrypsin, and aprotinin). Whole cell extracts were prepared by three cycles of freezing (-80°C) and thawing (0°C), clarified by centrifugation at 15,000 x g for 15 min at 4°C, and the supernatants were stored at -80°C (13)
. Protein concentration of each extract was determined using the Bio-Rad Protein Assay.
Each whole cell extract (500 µg protein) was suspended in 1 ml of buffer A [400 mM NaCl, 50 mM Tris acetate (pH 7.5), 1 mM DTT, 1% (v/v) Triton X-100, 1 mM PMSF, and 0.5 µg/ml each of leupeptin, pepstatin A, chymostatin, antitrypsin, and aprotinin] and precleared with addition of 2 mg of Protein G-Sepharose 4B (Sigma-Aldrich; previously equilibrated in buffer A), followed by incubation on a rotating platform for 45 min at 4°C. After centrifugation at 15,000 x g for 15 s at 4°C, 2 µg of a mouse monoclonal anti-hER antibody (clone B10; Ref. 13
) were added to the supernatant, and the sample was incubated for 30 min at 4°C. Then 4 mg of buffer A-washed Protein G-Sepharose 4B were added, and samples were rotated at 4°C for 60 min, followed by four washes with buffer A containing 0.2% (w/v) SDS (13)
. Retained immune-complexes were eluted by boiling in Laemmli sample buffer, and the protein concentration of each sample was determined using the Bio-Rad Protein assay. Each sample (50 µg protein) was separated by 4–12% gradient SDS-PAGE, and proteins were transferred by electroblotting onto nitrocellulose membranes. hER was detected with a mouse monoclonal anti-hER (clone B10) primary antibody 1 µg/ml in 5% nonfat dried milk powder in 150 mM NaCl, 10 mM Tris (pH 8.0), 0.05% (v/v) Tween 20 by overnight incubation at 4°C, followed by a goat antimouse IgG secondary antibody-alkaline phosphatase conjugate (Sigma-Aldrich). Immunodetection of acetylated hER was performed in a parallel incubation using a rabbit polyclonal anti-acetylated lysine antibody (a generous gift from C. Crane-Robinson) diluted 1:1000 in 5% nonfat dried milk powder in 150 mM NaCl, 10 mM Tris (pH 8.0), and 0.05% (v/v) Tween 20 by overnight incubation at 4°C, followed by goat antirabbit IgG F(ab')2 secondary antibody-alkaline phosphatase conjugate (Sigma-Aldrich). Color was visualized using a 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium substrate.
HDAC Assay.
Total cellular extracts were prepared from each breast cancer cell line (14)
. All procedures were performed at 4°C. Briefly, 2.5 x 106 cells were washed with ice-cold DPBS and resuspended in 200 µl of lysis buffer [120 mM NaCl, 50 mM Tris (pH 7.5), 5 mM EDTA, and 0.5% (v/v) NP40] in the presence of freshly added protease inhibitors (2 µg/ml aprotinin, 10 µg/ml chymostatin, 1 µg/ml leupeptin, 1 µg/ml pepstatin A, and 0.5 mM PMSF). After disruption in a Dounce homogenizer and brief sonication, total cell lysates were cleared by two rounds of centrifugation at 15,000 x g for 10 min, and the supernatants were stored at -80°C.
In vitro HDAC activity was assayed as described previously (14
, 15) . Briefly, 20 µl of crude cell extract (2.5 x 105 cells), in the presence of varying concentrations of TSA in 0.1% (v/v) ethanol or 0.1% (v/v) ethanol as vehicle control, were incubated for 60 min at 25°C with 1 µl (1.5 x 106 cpm) of [3H]acetyl-labeled histone H4 peptide substrate (NH2-terminal residues 2–20) that had been acetylated with [3H]acetic acid, sodium salt (3.7 GBq/mmol; New England Nuclear, Boston, MA) by an in vitro incorporation method (15)
. Each 200-µl reaction was quenched with 50 µl of 1 M HCl/0.16 M acetic acid and extracted with 600 µl of ethyl acetate, and released [3H]acetate was quantified by scintillation counting.
In Vivo Studies.
Inbred virgin female (Ludwig/Wistar/Olac) rats bearing tumors induced with NMU were supplied by Harlan (UK) Ltd. (Oxfordshire, United Kingdom). All animals were maintained and treated under Home Office license in accordance with the provisions of the Animals (Scientific Procedures) Act, 1986 of the United Kingdom. Experimental studies were conducted in the manner described previously (16)
on adult rats bearing tumors measuring between 10 and 20 mm in diameter. Tumor dimensions were determined weekly by measuring two diameters at right angles with Vernier calipers. Tumor volume was estimated using the following formula:
 |
For the initial dose-ranging evaluation, 5 animals each received a single dose of TSA ranging from 500 ng/kg to 5 mg/kg in 50 µl of DMSO by s.c. injection; one animal received 50 µl of DMSO by s.c. injection as a vehicle control.
Twelve rats were randomized to receive 500 µg/kg TSA in 50 µl DMSO, or 50 µl DMSO as vehicle control, by s.c. injection twice weekly for 4 weeks. In subsequent studies, 30 rats were randomized to receive TSA 500 µg/kg in 50 µl DMSO, or 50 µl DMSO as vehicle control, by s.c. injection daily for 4 weeks. Weekly tumor measurements, estimated tumor volumes, and body mass were recorded for each animal. Animals were sacrificed at the end of the 4-week study period; palpable tumors were resected and immediately snap-frozen in liquid nitrogen. Animals with tumors <2 cm in diameter or ulcerating tumors were withdrawn from study.
Histopathology.
Tumors were fixed overnight in 10% (v/v) formalin in 0.9% NaCl solution before paraffin embedding and routine sectioning. Three representative H&E-stained sections were examined from each tumor. Tumors were classified according to the WHO classification of rat mammary tumors (17)
.
Statistical Considerations.
The nonparametric Mann-Whitney U test was used for comparative statistical analysis of paired data and the Fisher’s exact test for comparison of groups. Statistical significance was defined at the 5% level ( = 0.05). The concentration of TSA that inhibited HDAC activity or cell proliferation by 50% (IC50) was determined graphically in each case using nonlinear regression analysis to fit inhibition data to the appropriate dose-response curve (GraphPad Prism version 2.0; GraphPad Software, Inc., San Diego, CA).
|
RESULTS AND DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
. After a 96-h incubation, the mean ± SD IC50 was 124.4 ± 120.4 nM (range, 26.4–308.1 nM). Interestingly, the cell lines that express ER (T-47D, MCF-7, BT-474, and ZR-75-1; immunohistochemical and reverse transcription-PCR, data not shown) were more sensitive to TSA (mean ± SD IC50, 47.5 ± 36.9 nM) than the ER-negative cell lines (SK-BR-3, CAL 51, MDA-MB-453, and MDA-MB-231; mean ± SD IC50, 201.2 ± 129.3 nM; P = 0.03, Mann Whitney U = 1). However, total HDAC inhibitory activity of TSA was similar (mean ± SD IC50, 2.4 ± 0.5 nM; range, 1.5–2.9 nM; Table 1
), and TSA treatment induced pronounced histone H4 hyperacetylation in all of the breast cancer cell lines (Fig. 1)
. Differential sensitivity of the ER-positive cell lines to TSA suggests that the mechanism of growth inhibition is different from cells that do not express functional ER. Although the explanation for this observation is still unclear, one possibility is that inhibition of HDAC activity by TSA might induce hyperacetylation of the ER itself, such as in the DNA-binding domain, which could affect dimerization of the receptor. In preliminary experiments, hER immunoprecipitated from lysates of MCF-7 cells grown in the presence and absence of TSA has been probed with an antibody to acetylated lysine residues in Western blot analysis and found to be hyperacetylated in response to TSA treatment (Fig. 2)
.
|
|
|
Further studies were then undertaken to optimize the schedule of TSA administration. Thirty rats were randomized, 16 to receive 500 µg/kg TSA in 50 µl of DMSO and 14 to receive 50 µl of DMSO as vehicle control by s.c. injection daily for 4 weeks. The effect of TSA administration on the growth of NMU-induced tumors is depicted in Fig. 3A
. TSA significantly inhibited tumor growth compared with control (Mann-Whitney U = 4.5, P = 0.04). Mean ± SE tumor volume of the control group increased by 260.4 ± 74.5% after 4 weeks, whereas the mean ± SE tumor volume of the TSA-treated animals was only 14.1 ± 26.6% greater after 4 weeks than at the commencement of the experiment. TSA treatment resulted in tumor regression in 12 of 16 rats compared with only 1 of 14 controls (P = 0.0002, Fisher’s exact test; Table 2
). Body mass of the TSA-treated rats did not differ significantly from controls (Mann-Whitney U = 8.5, P > 0.05; Fig. 3B
), confirming the observation that TSA did not cause serious systemic toxicity.
|
|
. Two control rats each had tumors with benign histology. Six tumors from 3 rats refractory to TSA treatment were examined; 5 were adenocarcinomas, whereas a sixth tumor was an anaplastic carcinoma (Fig. 4B)
. However, 19 tumors from 12 other animals that responded to TSA had a benign histological phenotype, either tubular adenoma (Fig. 4C)
or fibroadenoma (Fig. 4D)
. Although sequential tissue samples from individual animals were not obtained in the present study, the benign histology of most tumors in the TSA-treated group compared with the malignant phenotype of tumors in the majority of controls (P < 0.0001, Fisher’s exact test), suggests that induction of differentiation is the predominant mechanism of antitumor action of TSA.
|
-positive breast cancer cell lines in culture to the growth-inhibitory effects of TSA may be attributable to hyperacetylation of the ER. Because NMU-induced rat mammary carcinomas express functional ER (19)
and most are hormone responsive (20)
, it is possible that the observed antitumor activity of TSA in vivo in this model may similarly be mediated by inhibition of ER functional activity. In future experiments, it will be important to establish whether the anti-estrogen tamoxifen in combination with TSA has greater antitumor efficacy than either agent alone in this model. Another important question to be addressed in future work is whether TSA treatment can prevent the establishment of rat mammary tumors after administration of NMU. Further studies are currently in progress to evaluate the antitumor efficacy of TSA in nude mice xenograft models of ER-positive and ER-negative breast cancer. In the present studies, we have found that TSA is a potent inhibitor of breast cancer cell proliferation, inhibits HDAC activity in a dose-dependent manner, and induces pronounced histone H4 hyperacetylation. TSA has pronounced dose-dependent antitumor activity in vivo in the NMU-induced rat mammary carcinoma model when administered at a dose of 500 µg/kg by s.c. injection daily for 4 weeks. Furthermore, TSA does not cause any measurable toxicity in doses of up to 5 mg/kg by s.c. injection, a dose 10-fold higher than the effective antitumor dose in this model. Histological staining has shown a preponderance of cribiform/papillary adenocarcinoma in tumors that were resistant to TSA treatment and in control animals. However, in responding tumors, the predominant histological phenotype was benign tubular adenoma or fibroadenoma, suggesting that the antitumor effects of TSA may have resulted from induction of differentiation. The present studies therefore confirm that TSA has potent dose-dependent antitumor activity against breast cancer in vitro and in vivo, strongly supporting HDAC as a molecular target for anticancer therapy in breast cancer. Together with the pronounced antitumor activity of TSA and striking absence of toxicity in this carcinogen-induced mammary cancer model, these observations provide a rational basis for further Phase I development of TSA in the treatment of human breast cancer. Because TSA also has potent cytostatic activity in a wide range of solid tumor and hematological cell lines in culture, further studies are needed to characterize the antitumor activity of TSA in vivo in other tumor types.
|
FOOTNOTES |
|---|
1 Supported by the Cancer Research Campaign. Presented at the 1999 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Washington, DC (Clin. Cancer Res., 5: 3777s, 1999). 
2 To whom requests for reprints should be addressed, at Department of Cancer Medicine, Cancer Research Campaign Laboratories, 5th Floor MRC Cyclotron Building, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-208-383-8370; Fax: 44-208-383-5830; E-mail: d.vigushin{at}ic.ac.uk
3 The abbreviations used are: HDAC, histone deacetylase; TSA, trichostatin A; NMU, N-methyl-N-nitrosourea; IC50, 50% inhibitory concentration; PMSF, phenylmethylsulfonyl fluoride; ER, estrogen receptor; hER, human ER.
Received 10/11/00; revised 12/26/00; accepted 1/16/01.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
by protein kinase A regulates dimerization. Mol. Cell. Biol., 19: 1002-1015, 1999.Commentary
This article has been cited by other articles:
|
|
 |
|
  V. Duong, C. Bret, L. Altucci, A. Mai, C. Duraffourd, J. Loubersac, P.-O. Harmand, S. Bonnet, S. Valente, T. Maudelonde, et al. Specific Activity of Class II Histone Deacetylases in Human Breast Cancer Cells Mol. Cancer Res., December 1, 2008; 6(12): 1908 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, P. Hao, S. Zheng, K. Tu, H. Fan, R. Zhu, G. Ding, C. Dong, C. Wang, X. Li, et al. Gene expression module-based chemical function similarity search Nucleic Acids Res., November 1, 2008; 36(20): e137 - e137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Malinen, A. Saramaki, A. Ropponen, T. Degenhardt, S. Vaisanen, and C. Carlberg Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1{alpha},25-dihydroxyvitamin D3 Nucleic Acids Res., January 17, 2008; 36(1): 121 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Krusche, A. J. Vloet, I. Classen-Linke, U. von Rango, H. M. Beier, and J. Alfer Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas Hum. Reprod., November 1, 2007; 22(11): 2956 - 2966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoue, M. Kobayashi, K. Yano, M. Miura, A. Izumi, C. Mataki, T. Doi, T. Hamakubo, P. C. Reid, D. A. Hume, et al. Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2652 - 2659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sharma, N. K. Saxena, N. E. Davidson, and P. M. Vertino Restoration of Tamoxifen Sensitivity in Estrogen Receptor-Negative Breast Cancer Cells: Tamoxifen-Bound Reactivated ER Recruits Distinctive Corepressor Complexes. Cancer Res., June 15, 2006; 66(12): 6370 - 6378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Joung, K. N. Min, J. Y. An, D.-K. Kim, G. Kong, and Y. Y. Sheen Potent In vivo Anti-Breast Cancer Activity of IN-2001, a Novel Inhibitor of Histone Deacetylase, in MMTV/c-Neu Mice. Cancer Res., May 15, 2006; 66(10): 5394 - 5402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Mukhopadhyay, E. Weisberg, D. Gilchrist, R. Bueno, D. J. Sugarbaker, and M. T. Jaklitsch Effectiveness of Trichostatin A as a Potential Candidate for Anticancer Therapy in Non-Small-Cell Lung Cancer. Ann. Thorac. Surg., March 1, 2006; 81(3): 1034 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Choi, K.-H. Nam, J. Kim, M. W. Baek, J.-E. Park, H.-Y. Park, H. J. Kwon, O.-S. Kwon, D.-Y. Kim, and G. T. Oh Trichostatin A Exacerbates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2404 - 2409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Danzi, P. Dubon, and I. Klein Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1506 - H1511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Drummond, C. Marx, Z. Guo, G. Scott, C. Noble, D. Wang, M. Pallavicini, D. B. Kirpotin, and C. C. Benz Enhanced Pharmacodynamic and Antitumor Properties of a Histone Deacetylase Inhibitor Encapsulated in Liposomes or ErbB2-Targeted Immunoliposomes Clin. Cancer Res., May 1, 2005; 11(9): 3392 - 3401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hu and N. H. Colburn Histone Deacetylase Inhibition Down-Regulates Cyclin D1 Transcription by Inhibiting Nuclear Factor-{kappa}B/p65 DNA Binding Mol. Cancer Res., February 1, 2005; 3(2): 100 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Alao, E. W-F. Lam, S. Ali, L. Buluwela, W. Bordogna, P. Lockey, R. Varshochi, A. V. Stavropoulou, R. C. Coombes, and D. M. Vigushin Histone Deacetylase Inhibitor Trichostatin A Represses Estrogen Receptor {alpha}-Dependent Transcription and Promotes Proteasomal Degradation of Cyclin D1 in Human Breast Carcinoma Cell Lines Clin. Cancer Res., December 1, 2004; 10(23): 8094 - 8104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Sanderson, G. W. Taylor, E. O. Aboagye, J. P. Alao, J. R. Latigo, R. C. Coombes, and D. M. Vigushin PLASMA PHARMACOKINETICS AND METABOLISM OF THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AFTER INTRAPERITONEAL ADMINISTRATION TO MICE Drug Metab. Dispos., October 1, 2004; 32(10): 1132 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Reilly, N. Mishra, J. M. Miller, D. Joshi, P. Ruiz, V. M. Richon, P. A. Marks, and G. S. Gilkeson Modulation of Renal Disease in MRL/lpr Mice by Suberoylanilide Hydroxamic Acid J. Immunol., September 15, 2004; 173(6): 4171 - 4178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Druesne, A. Pagniez, C. Mayeur, M. Thomas, C. Cherbuy, P.-H. Duee, P. Martel, and C. Chaumontet Diallyl disulfide (DADS) increases histone acetylation and p21waf1/cip1 expression in human colon tumor cell lines Carcinogenesis, July 1, 2004; 25(7): 1227 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-H. Leu, H. H. Yeh, C.-C. Huang, Y.-C. Chuang, S. L. Su, and M.-C. Maa Participation of p97Eps8 in Src-mediated Transformation J. Biol. Chem., March 12, 2004; 279(11): 9875 - 9881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. L. Chung, A.-J. Wang, and L.-F. Yao Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy Mol. Cancer Ther., March 1, 2004; 3(3): 317 - 325. [Abstract] [Full Text]
|
|
|
|
|
|
N. Takai, J. C. Desmond, T. Kumagai, D. Gui, J. W. Said, S. Whittaker, I. Miyakawa, and H. P. Koeffler Histone Deacetylase Inhibitors Have a Profound Antigrowth Activity in Endometrial Cancer Cells Clin. Cancer Res., February 1, 2004; 10(3): 1141 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Grassi, P. Maccaroni, R. Meyer, H. Kaiser, E. D'Ambrosio, E. Pascale, M. Grassi, A. Kuhn, P. Di Nardo, R. Kandolf, et al. Inhibitors of DNA methylation and histone deacetylation activate cytomegalovirus promoter-controlled reporter gene expression in human glioblastoma cell line U87 Carcinogenesis, October 1, 2003; 24(10): 1625 - 1635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Grisolano, J. O'Neal, J. Cain, and M. H. Tomasson An activated receptor tyrosine kinase, TEL/PDGF{beta}R, cooperates with AML1/ETO to induce acute myeloid leukemia in mice PNAS, August 5, 2003; 100(16): 9506 - 9511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Antos, T. A. McKinsey, M. Dreitz, L. M. Hollingsworth, C.-L. Zhang, K. Schreiber, H. Rindt, R. J. Gorczynski, and E. N. Olson Dose-dependent Blockade to Cardiomyocyte Hypertrophy by Histone Deacetylase Inhibitors J. Biol. Chem., August 1, 2003; 278(31): 28930 - 28937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hemminki, A. Kanerva, B. Liu, M. Wang, R. D. Alvarez, G. P. Siegal, and D. T. Curiel Modulation of Coxsackie-Adenovirus Receptor Expression for Increased Adenoviral Transgene Expression Cancer Res., February 15, 2003; 63(4): 847 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Tang and G. G. Maul Mouse Cytomegalovirus Immediate-Early Protein 1 Binds with Host Cell Repressors To Relieve Suppressive Effects on Viral Transcription and Replication during Lytic Infection J. Virol., December 20, 2002; 77(2): 1357 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Elaut, G. Torok, M. Vinken, G. Laus, P. Papeleu, D. Tourwe, and V. Rogiers Major Phase I Biotransformation Pathways of Trichostatin A in Rat Hepatocytes and in Rat and Human Liver Microsomes Drug Metab. Dispos., December 1, 2002; 30(12): 1320 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Strait, B. Dabbas, E. H. Hammond, C. T. Warnick, S. J. Ilstrup, and C. D. Ford Cell Cycle Blockade and Differentiation of Ovarian Cancer Cells by the Histone Deacetylase Inhibitor Trichostatin A Are Associated with Changes in p21, Rb, and Id Proteins Mol. Cancer Ther., November 1, 2002; 1(13): 1181 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lim, I. Han, H. J. Kwon, and E.-S. Oh Trichostatin A-induced Detransformation Correlates with Decreased Focal Adhesion Kinase Phosphorylation at Tyrosine 861 in ras-transformed Fibroblasts J. Biol. Chem., April 5, 2002; 277(15): 12735 - 12740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Scott, C. Marden, F. Xu, L. Kirk, and C. C. Benz Transcriptional Repression of ErbB2 by Histone Deacetylase Inhibitors Detected by a Genomically Integrated ErbB2 Promoter-reporting Cell Screen Mol. Cancer Ther., April 1, 2002; 1(6): 385 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-H. Chang and E. Szabo Enhanced Growth Inhibition by Combination Differentiation Therapy with Ligands of Peroxisome Proliferator-activated Receptor-{gamma} and Inhibitors of Histone Deacetylase in Adenocarcinoma of the Lung Clin. Cancer Res., April 1, 2002; 8(4): 1206 - 1212. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
). Bars, SE. B, effect of TSA on body mass of rats bearing NMU-induced mammary tumors. Results are expressed as the percentage change from the mean body mass at the start of the experiment for TSA-treated (•) and vehicle control groups (