| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Cell and Molecular Biology Section, Pediatric Oncology Branch [J. J., J. W., H. H., C. K., C. J. T.] and the Experimental Therapeutics Branch [R. R., S. E. B.], Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, and Department of Pathology, Seoul National University of Medicine, Seoul, Korea 100-799 [C. J. K.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and PLZF-RAR) have been found to repress transcription of target genes such as the RARß gene. Transcriptional corepressor complexes contain HDAC activity and transcriptional coactivator complexes contain histone acetyltransferase activity. Recent studies indicate that HDAC inhibitors such as trichostatin A or NaBu are able to relieve the transcriptional repression caused by the chimeric transcription factors PML-RARa and PLZF-RARa (8
, 9)
. HDAC inhibitors alone or in combination with retinoids have been shown to induce leukemia remission and prolonged survival in an animal model of acute promyelocytic leukemia without apparent side effects (10)
. Acetylation and deacetylation of histones alter higher order chromatin structure by influencing histone interaction with DNA (11 , 12) . Transcription factors may also be acetylated (13) , and the acetylated status of these proteins may influence their interaction with DNA, as well as their ability to interact with other transcriptional coregulatory proteins. For example, acetylation of p53 enhances its sequence-specific DNA binding activity (14 , 15) . Deacetylated histones are associated with cell growth, whereas hyperacetylated histones (16 , 17) are associated with cell growth arrest, differentiation, and/or apoptosis. Finally, tubulin can be acetylated, and this may affect the dynamic equilibrium between soluble and polymerized tubulin and the structure of microtubules (18) .
HDAC inhibitors differ with regards to their antitumor activity, toxicity, and stability (17 , 19) . High concentrations of NaBu are required to induce tumor cell apoptosis or differentiation (20) . Additionally, NaBu has a short half-life that limits its effectiveness as a therapeutic agent. Hybrid polar compounds such as M-carboxycinnamic acid bishydroxamide have been shown to induce apoptosis in NB cells in vitro, although the mechanism has not been fully elucidated (21) . Saito et al. (22) recently evaluated the efficacy of MS-275, a synthetic benzene derivative that inhibits HDAC. In a number of adult tumor cell lines, MS-275 inhibited tumor cell growth with an IC50 in the submicromolar range. The inhibition of cell growth was accompanied by a cell cycle arrest and an induction of the cell cycle inhibitor p21. MS-275 administered p.o. inhibited the growth of established adult tumor lines s.c. implanted in nude mice with minimal toxicities.
To date, there have been few studies (21 , 23) using HDAC inhibitors in pediatric solid tumors, although these tumors are marked by alterations in the expression and structure of transcription factors. In this study, we assessed the antitumor activity of MS-275 against several pediatric solid tumor cell lines in vitro and against selected in vivo orthotopic xenograft murine models of pediatric solid tumors. We found that MS-275 inhibited in vitro cell growth in all cell lines tested with an IC50 ranging from 50 nM to 1.3 µM. In NB, EWS, and US orthotopic murine xenograft models, the oral administration of MS-275 inhibited tumor growth with few side effects.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. All cell lines were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, 2 mM glutamine, 50 units/ml penicillin, and 50ug/ml streptomycin at 37°C with 5% CO2 as described previously (26)
. N-(2-Aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl) aminomethyl] benzamide (MS-275) was kindly provided by Nihon Schering and was made as a 200 mM stock solution in 100% DMSO.
|
were seeded into 96 flat-bottomed well plates, and six replicate wells were incubated with different concentrations of MS-275 for 72 h. Twenty-four h before termination of culture, cells were incubated with 1 uCi of [3H]thymidine, cultured for an additional 16 h, and harvested with Packard FilterMate harvester (Packard Instrument Company, Meriden, CT). [3H]Thymidine was assessed in a Packard Top Count-NXT Scintillation counter (Packard Instrument Company). Two to four dose response curves were established for each cell line, and the variability among experiments on the same cell line was <10%. For the cell cycle, cells were mechanically detached at the indicated time after drug treatment, washed twice in ice-cold PBS, and processed for cell cycle analysis as described previously (24)
. TUNEL analyses were using the ApoDirect kit as per manufacturer’s recommendation (BD-PharMingen, Mountain View, CA).
Ac-H3 Analysis.
For acetylated histone assessment by Western analysis, cells were trypsinized, washed twice with PBS, resuspended in lysis buffer [0.02 M Tris (pH 7.4), 0.2 mM Triton X-100, and 0.02% 2-mercaptoethanol] with 2 ng/ml aprotinin, and solubilized by sonication. Protein extracts (10 µg) were subjected to SDS-PAGE and transferred to polyvinylidene difluoride membranes. Membranes were probed with Ac-H3 (Upstate Biotechnology, Lake Placid, NY). Glyceraldehyde-3-phosphate dehydrogenase (American Research Products, Belmont, MA) was used as a control. Cytospins of trypsinized cells were fixed in 95% ethanol/5% acetic acid and blocked in 8% BSA in PBS. After an overnight incubation with anti- Ac-H3, cells were stained with horse antirabbit FITC-conjugated secondary antibody (Vector Laboratories, Burlingame, CA) and counterstained with TO-PRO-3 iodide (Molecular Probes, Eugene, OR). Slides were scanned using a CompuCyte Laser Scanning Cytometer equipped with WinCyte software (Cambridge, MA).
RNA Preparation and Northern Blot Analysis.
Control and MS-275-treated cells were detached mechanically from the 150-cm2 plate, washed twice with ice-cold PBS, and processed for RNA extraction with the RNAeasy kit (Qiagen, Inc., Chatsworth, CA) according to the manufacturer’s instructions and analyzed by Northern blot analysis as described previously (24)
. Probes were labeled with [32P]dCTP using RediPrime II (Amersham Pharmacia Biotech) according to manufacturers recommendations.
In Vivo Animal Model.
The US (2 million) cells and the EWS cell line (TC71; 2 million cells) were injected orthotopically into the gastrocnemous muscle of SCID-beige mice. The NB cell line (KCNR; 2 million cells) was injected into the periadrenal fat pad of SCID-beige mice as described previously (28)
. Treatment was initiated 1 week after injection for KCNR cells when US tumors had reached 0.3 cm3 and when the TC71 cells reached 0.6 cm3. MS-275 was dissolved in 0.05 N HCl and 0.1% Tween in PBS and diluent served as placebo. Drug doses and scheduling were based on a maximally tolerated dose from murine studies on adult tumor cell lines (22)
. MS-275 and placebo were administered p.o. once daily 5 days/week for 4 weeks for US (5–8 animals in each treatment group) and KCNR (12 animals in each treatment group) and daily for 2 weeks for TC71 (10 animals in each treatment group). KCNR tumors were palpated daily for size, whereas the US and TC71 tumors were measured using a vernier caliper, and tumor volume was determined as described previously (28)
. A post test-Bonferroni’s multiple comparison test was used to assess the differences in the US and TC71 experiment, and an unpaired t test was used to assess the differences in the KCNR experiment.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Treatment of several adult tumor cell lines with MS-275 results in a dose-dependent decrease in cell viability (22)
. To assess whether MS-275 alters DNA synthesis in pediatric tumor cell lines, cells were seeded into a 96-well flat-bottomed plate and cultured with various concentrations of MS-275 for 72 h. MS-275 inhibited [3H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined (a representative of two to four experiments from each cell line is plotted in Fig. 1
). The MS-275 IC50s ranged from 50 nM for medulloblastoma cell line D283 to 1.3 µM for an US cell line (Table 1)
. MS-275 inhibits DNA synthesis in the osteosarcoma cell line HOS and a retinoblastoma cell line SK, which lacks RB. The RH cell line RD retains sensitivity to MS-275, although it contains a mutation in exon 2 of p53 and shows alterations in DNA damage responses (26
, 29)
. All of the tumor cell lines were more sensitive to the growth inhibiting effects of MS-275 than NIH3T3, an immortalized rodent fibroblast cell line (Table 1)
.
|
).
|
. For the KCNR cells, there was an increase in cells with a sub-G1 content of DNA. An increase in G1 was detected in Rh30 and G401. In Rh30, the increase in cells in G1 was accompanied by an increase in cells with a sub-G1 content of DNA. At 48 h, KCNR, TC106, and US had an increase in the percentage of cells with a sub-G1 content of DNA and decreases in the other phases of the cell cycle. U20S showed a transient accumulation of cells in G2-M at 24 h followed by an increase in cells in modest increase in cells in G1 at 48 h.
|
, left panel), whereas in TC106, there was a 3-fold increase in FITC-dUTP-labeled DNA (Fig. 3
, left panel). These data indicate that in the KCNR and TC106 cell lines, MS-275 induces apoptosis. It is likely that in the other cell lines in which MS-275 induces an increase in cells with a sub-G1 content of DNA, this is attributable to the induction of apoptosis.
|
, we have shown the Western analysis of three cell lines with different sensitivities to MS-275. At 4 h, the increases in Ac-H3 occur at 10–100 nM in TC32 cell line (IC50 = 100 nM), 100–500 nM for SK-N-AS (IC50 = 660 nM), and at 500-1000 nM in TC71 (IC50 = 1000 nM; Fig. 4A
). However, by 18 h maximum, Ac-H3 is detected even at low doses of MS-275.
|
. However, in the less MS-275 sensitive US cell line, the relative fluorescent intensity was 3.5, unchanged at 4 h, and only slightly increased to 4.43 at 18 h, indicating that there was not a dramatic increase in Ac-H3 under these conditions.
MS-275 Induced Changes in Gene Expression in Pediatric Tumors.
Other HDAC inhibitors (30)
as well as MS-275 (22)
have been shown to induce p21. We evaluated induction of p21 in selected pediatric tumor cell lines and found that in six of seven cell lines, there was an increase in p21 that occurred from 4–18 h after treatment with 1 µM MS-275 (Fig. 5A)
. Induction of p21 occurred regardless of the p53 status. Rh30 has an Arg to Ser mutation in codon 280 of p53 and shows a marked induction of p21 within hours of treatment with MS-275. The US cell line, which was the least sensitive to MS-275, did not show an increase in or induction of p21 under these conditions, but p21 was induced using 3 µM MS-275 (data not shown).
|
. Quantitative PCR indicated that the expression of the EWS/fli did not significantly change after MS-275 treatment (data not shown). This indicates that despite the presence of the chimeric transcription factor that represses TGF-ßRII expression, MS-275 treatment of cells can lead to an increase in TGF-ßRII expression. Most EWS cell lines constitutively express one of the TGF-ß isoforms constitutively (32)
. To assess whether the TGF-ß pathway was active after MS-275 treatment, the expression of a downstream target of the TGF-ß signaling path, PAI, was assessed. The pattern of PAI expression indicated that there was an early increase that occurred within 4 h of MS-275 treatment and before the detection of an increase in expression of TGF-ßRII. However, a second increase in PAI expression could be detected that was coincident or subsequent to the MS-275-induced increase in TGF-ßRII expression. These data are consistent with the hypothesis that the TGF-ß signaling path becomes active in these cells after MS-275 treatment.
Patients with NB tumors that contain amplification and overexpression of N-myc have a poor prognosis (33)
. We evaluated the expression of N-myc in NB cells treated with 1 µM MS-275 for various times. Within 4 h of MS-275 treatment, there was a decrease in N-myc levels, and expression was barely detected at 48 h (Fig. 5C)
. Similar results have been detected in an additional 4 of 4 N-myc-amplified NB cell lines examined (data not shown). In contrast, c-myc levels were increased in the EWS cells after treatment with MS-275. Thus, there is differential regulation of members of the myc gene family after treatment with MS-275.
Antitumor Effect of MS-275 in Tumor-bearing SCID-Beige Mice.
MS-275 has been shown to be effective in inhibiting the in vivo growth of most of the adult tumor cell lines grown s.c. in nude mice (22)
. To evaluate effects of MS-275 on the in vivo growth of the US cell line, which was most resistant to the effects of MS-275 in vitro, 2 x 106 US cells were injected into the gastrocnemious muscle and allowed to grow until the tumor reached 0.3 cm3. At that time (
5 days), the animals received various doses of MS-275 ranging from 8.25 to 24.5 mg/kg based on doses in the murine study of adult tumor cell lines that did not have significant toxicity. Both control and MS-275 tumors grew during the course of therapy. However, at the termination of therapy (4 weeks), the volume of the tumors in the MS-275 animals was decreased compared with controls. There was a 60% decrease in tumor volume in the animals treated with the maximal dose (24.5 mg/kg/day every 5 days) of MS-275 (Fig. 6A)
Using a Bonferroni’s multiple comparison test, (34)
only the US tumor size in the 24.5 mg/kg was significantly different (P < 0.001) from the size of the US tumors in the untreated group.
|
. The mean tumor volume in mice that received 24.5 mg/kg MS-275 was relatively unchanged from initiation of therapy. Using a Bonferroni’s multiple comparison test, both the TC71 tumor size in the 24.5 mg/kg and the 12.5 mg/kg group were significantly different (P < 0.001) from the size of the TC71 tumors in the untreated group. One mouse in the control group was lost because of a gavage accident.
The NB cell line KCNR (2 x 106cells) was injected orthotopically to the adrenal gland of 18 mice. After 1 week, 2 animals were sacrificed, and small periadrenal masses could be visualized (28)
. Remaining animals were randomly placed into two groups, and 24.5 mg/kg MS-275 (12 mice) or diluent (10 mice) were administered by oral gavage five times/week. After 1 month, when the tumor volume in the placebo cohort had reached 1.5 cm3 (as determined by external palpation), the animals were sacrificed, and tumors were excised, measured, and weighed. In the placebo group, all animals had tumors, and the tumor volume ranged from 1 to 7 cm3 with a mean tumor volume of 3.5 cm3. In contrast, only 50% of animals had a visually detectable tumor in the MS-275 group, and the volume of these tumors ranged from 0.6 to 2.7 cm3, which was significantly different from the controls (P = 0.0009 using an unpaired t test; Fig. 6C
). NB tumors and xenografts growth in orthotopic sites in SCID-beige mice are highly vascular; KCNR tumors in the placebo group are also well vascularized (Fig. 7A)
. In the MS-275-treated group, there was a marked decrease in vascularization (Fig. 7B)
. Consistent with in vitro studies, there was a decrease in N-myc mRNA and an increase in p21mRNA in tumors from mice treated with MS-275 compared with control (inset panel on Fig. 7
).
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. However, as in the study on adult tumor cell lines, we found that concentrations of MS-275 significantly less than the IC50 were able to induce increases in Ac-H3 after 24 h. In contrast to adult studies in which MS-275 induced a G1 arrest in all cell lines examined, the effects of MS-275 on cell growth and induction of apoptosis were varied among the different pediatric tumor cell lines evaluated. In some cell lines, apoptosis was induced, whereas in others, cell cycle arrest occurred in either the G1 or G2 phase of the cell cycle. The variability in response of the cell lines to the drug may reflect the nature of the genetic alterations and the signal transduction paths altered in the different cell lines. As has been shown for a number of HDAC inhibitors, p21WAF/CIP1 was induced in most of the pediatric solid tumor cell lines evaluated irrespective of the p53 status of the cells. This suggests that HDAC inhibitors as a class may induce cell death irrespective of the status of p53.
Although we cannot exclude that there is a common mechanism by which MS-275 affects the growth and survival of different tumor cell lines, it is equally possible that the effect of MS-275 on the different pediatric solid tumor cell lines may be dependent on the nature of the genetic alteration in the different tumor cell lines. We evaluated changes in TGF-ßRII mRNA, which is known to be transcriptionally repressed by the EWS/FLI transcription factor in EWS and the N-myc gene whose amplification is associated with a poor prognosis in NB tumors. Studies on MS-275 indicate that it induces the expression of TGF-ßRII mRNA and restores TGF-ß signaling in breast cancer cell lines (35) . We have found that in EWS in which the chimeric transcription factor EWS/FLI transcriptionally represses the TGF-ßRII gene (31) , MS-275 is able to stimulate increases in TGF-ßRII mRNA despite the presence of the EWS/FLI transcriptional repressor. Our finding that there is an increase in PAI mRNA, a downstream target of the TGF-ß signal transduction path coincident or subsequent to the MS-275-induced increase in TGF-ßRII mRNA, is consistent with the restoration of TGF-ß signaling in EWS. Previous studies indicate that restoration of the TGF-ß path in EWS cell lines inhibits their growth in animal models (31) . Additional studies will be needed to assess whether the effects of MS-275 on the growth of TC71 cells in vivo are dependent on the induction of TGF-ßRII and restoration of the TGF-ß signal transduction path.
Previous studies using the HDAC inhibitor CHBA have indicated induction of p21 in NB cell lines and inhibition of NB tumor growth in vitro and in vivo (21
, 23)
. Our results using MS-275 are similar. Typically, the use of HDAC inhibitors has been found to increase gene expression, whereas repression of gene expression by HDAC inhibitors is not common. In N-myc-amplified NB cells, we found that MS-275 induced a decrease in N-myc mRNA expression (Fig. 5
and data not shown), and similar findings were found in tumors taken from animals treated with MS-275 (Fig. 7)
. Decreases in N-myc are known to affect the survival and growth of NB cells (36
, 37)
. Although this may affect the biology of N-myc-expressing tumor cell lines, we also found that MS-275 was able to inhibit the growth of a non-N-myc-amplified cell line, SK-N-AS. Thus the mechanism by which MS-275 affects NB cell growth and survival may not require N-myc down-regulation or may be distinct in different NB cell types. However, both KCNR and AS contain 1pLOH and increases in 17q, common although uncharacterized genetic lesions in NB, and it is possible that MS-275 may complement these genetic alterations to alter NB cell growth.
In our animal studies, we found that the growth of established tumors in vivo was markedly affected by treatment with MS-275. Toxicities were minimal with ruffled fur being the consistent alteration noted in all of the experiments. Initial studies indicated that 24.5 mg/kg every 5–7 days by oral gavage was the most effective dose even in the US cell line. In the NB and EWS models, tumor growth was markedly altered and in some cases there was no detectable tumor at the highest drug concentrations. The mechanism by which the drug affects tumor growth in vivo remains to be elucidated. Recent studies indicate that HDAC inhibitors may affect angiogenesis (38
, 39)
and, in the NB model preliminary analysis indicated, a decrease in tumor angiogenesis (Fig. 7)
. Current studies are aimed at more precisely detailing the changes in angiogenesis and metastasis in the xenograft tumor models.
In this report we have evaluated the in vitro and in vivo effects of the HDAC inhibitor MS-275 in a number of pediatric solid tumor cell lines. Future studies on the changes in gene expression induced by MS-275 has the potential to reveal genes with expressions that are affected by the altered transcription factors in these different pediatric solid tumors. As in vitro studies indicated that MS-275 induced apoptosis in many cases, histological and molecular genetic analysis of the xenograft tumors will enable us to determine whether induction of apoptosis and/or inhibition of angiogenesis affects tumor growth in vivo. Currently, MS-275 is in Phase I clinical trials in adults and these studies indicate that it should be considered for the treatment of pediatric malignancies as well.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 These individuals contributed equally to this work. 
2 J. J. is a M.D./Ph.D. student from Howard University, College of Medicine doing his thesis work in the Cell and Molecular Biology Section/Pediatric Oncology Branch/Center for Cancer Research/National Cancer Institute.
3 To whom requests for reprints should be addressed, at National Cancer Institute, Building 10, Room 13N240, 10 Center Drive, MSC 1928, Bethesda, MD 20892. Phone: (301) 496-1543; Fax: (301) 402-0575; E-mail: ct47a{at}nih.gov
4 The abbreviations used are: NB, neuroblastoma; EWS, Ewing’s sarcoma; RH, rhabdomyosarcoma; HDAC, histone deacetylase; NaBu, sodium n-butyrate; MS-275, MS-27-275; US, undifferentiated sarcoma; TdT, terminal deoxytransferase; TUNEL, Tdt-mediated nick end labeling; Ac-H3, acetylated histone H3; PAI, plasminogen activator inhibitor.
Received 3/28/02. Accepted 9/ 5/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-tubulin and its relationship to the assembly and disassembly of microtubules. J. Cell Biol., 103: 571-579, 2001.
-irradiation and altered cell cycle regulation by insulin-like growth factor II overexpression. J. Biol. Chem., 274: 13118-13126, 1999.This article has been cited by other articles:
|
|
 |
|
  S. Liu, H. Cheng, W. Kwan, J. M. Lubieniecka, and T. O. Nielsen Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models Mol. Cancer Ther., June 1, 2008; 7(6): 1751 - 1761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Di Bartolo, M. Cannon, Y.-F. Liu, R. Renne, A. Chadburn, C. Boshoff, and E. Cesarman KSHV LANA inhibits TGF-{beta} signaling through epigenetic silencing of the TGF-{beta} type II receptor Blood, May 1, 2008; 111(9): 4731 - 4740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Slater and J. Shipley Clinical relevance of molecular genetics to paediatric sarcomas J. Clin. Pathol., November 1, 2007; 60(11): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. De los Santos, A. Zambrano, A. Sanchez-Pacheco, and A. Aranda Histone Deacetylase Inhibitors Regulate Retinoic Acid Receptor {beta} Expression in Neuroblastoma Cells by Both Transcriptional and Posttranscriptional Mechanisms Mol. Endocrinol., October 1, 2007; 21(10): 2416 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Di Renzo, M. L. Broccia, E. Giavini, and E. Menegola Relationship between Embryonic Histonic Hyperacetylation and Axial Skeletal Defects in Mouse Exposed to the Three HDAC Inhibitors Apicidin, MS-275, and Sodium Butyrate Toxicol. Sci., August 1, 2007; 98(2): 582 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Keshelava, E. Davicioni, Z. Wan, L. Ji, R. Sposto, T. J. Triche, and C. P. Reynolds Histone Deacetylase 1 Gene Expression and Sensitization of Multidrug-Resistant Neuroblastoma Cell Lines to Cytotoxic Agents by Depsipeptide J Natl Cancer Inst, July 18, 2007; 99(14): 1107 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. De los Santos, A. Zambrano, and A. Aranda Combined effects of retinoic acid and histone deacetylase inhibitors on human neuroblastoma SH-SY5Y cells Mol. Cancer Ther., April 1, 2007; 6(4): 1425 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Gojo, A. Jiemjit, J. B. Trepel, A. Sparreboom, W. D. Figg, S. Rollins, M. L. Tidwell, J. Greer, E. J. Chung, M.-J. Lee, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias Blood, April 1, 2007; 109(7): 2781 - 2790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yang, Y. Tian, S. Liu, R. Zeine, A. Chlenski, H. R. Salwen, J. Henkin, and S. L. Cohn Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma Cancer Res., February 15, 2007; 67(4): 1716 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Gastaldi, P. Bonvini, F. Sartori, A. Marrone, A. Iolascon, and A. Rosolen Plakoglobin is differentially expressed in alveolar and embryonal rhabdomyosarcoma and is regulated by DNA methylation and histone acetylation Carcinogenesis, September 1, 2006; 27(9): 1758 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Noh, E. R. Jang, G. Jeong, Y. M. Lee, C. K. Min, and J.-S. Lee Methyl CpG-Binding Domain Protein 3 Mediates Cancer-Selective Cytotoxicity by Histone Deacetylase Inhibitors via Differential Transcriptional Reprogramming in Lung Cancer Cells Cancer Res., December 15, 2005; 65(24): 11400 - 11410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mitic and J. S. Mckay Immunohistochemical Analysis of Acetylation, Proliferation, Mitosis, and Apoptosis in Tumor Xenografts Following Administration of a Histone Deacetylase Inhibitor--A Pilot Study Toxicol Pathol, December 1, 2005; 33(7): 792 - 799. [Abstract] [PDF]
|
|
|
|
|
|
M. Entin-Meer, A. Rephaeli, X. Yang, A. Nudelman, S. R. VandenBerg, and D. A. Haas-Kogan Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas Mol. Cancer Ther., December 1, 2005; 4(12): 1952 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Acharya, A. Sparreboom, J. Venitz, and W. D. Figg Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review Mol. Pharmacol., October 1, 2005; 68(4): 917 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. C. Ryan, D. Headlee, M. Acharya, A. Sparreboom, J. B. Trepel, J. Ye, W. D. Figg, K. Hwang, E. J. Chung, A. Murgo, et al. Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma J. Clin. Oncol., June 10, 2005; 23(17): 3912 - 3922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Subramanian, A. W. Opipari Jr., X. Bian, V. P. Castle, and R. P. S. Kwok Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors PNAS, March 29, 2005; 102(13): 4842 - 4847. [Abstract] |
), 8.25 (
), 16.25 (
), or 24.5 (
) mg/kg MS-275 by oral gavage 5 days/week for 4 weeks. B, effect of on the growth of the TC71 EWS cells implanted into the gastrocnemious muscle of SCID-beige mice. Mice received diluent (