This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Coffey, D. C. Articles by La Quaglia, M. P. Search for Related Content PubMed PubMed Citation Articles by Coffey, D. C. Articles by La Quaglia, M. P.

The Histone Deacetylase Inhibitor, CBHA, Inhibits Growth of Human Neuroblastoma Xenografts in Vivo, Alone and Synergistically with All-Trans Retinoic Acid¹

Departments of Pediatrics [D. C. C., M. C. K.] and Surgery [R. D. G.], Joan and Sanford I. Weill Graduate School of Medical Sciences of Cornell University, and Departments of Pediatrics [D. C. C], Cell Biology [L. M. B., R. A. R., P. A. M., V. M. R.], Biostatistics [G. H.], and Pediatric Surgery [M. P. L. Q.], Sloan-Kettering Institute and Memorial Sloan-Kettering Cancer Center, New York, New York 10021

	ABSTRACT

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.

	Introduction

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Neuroblastoma, the most common extracranial solid tumor of childhood, accounts for more than 15% of cancer-related deaths in this age group (1) . The high mortality of advanced-stage disease has spurred active investigation of new agents with therapeutic potential. Recently, a series of HDACIs⁴ (2) , at micromolar concentrations, has been shown to induce differentiation and/or apoptosis of a variety of transformed cell lines (reviewed in Ref. 3 ). We have demonstrated previously that the HDACI, CBHA, causes apoptosis of neuroblastoma cells in vitro (4) . HDACs together with histone acetyltransferases (e.g., CBP/p300) regulate the acetylation state of nucleosomal histones, thereby altering chromatin structure (5 , 6) . It has been proposed that these structural changes regulate the transcription of target genes causing the induction of differentiation or apoptosis in transformed cells.

HDACs and histone acetyltransferases are components of multiprotein complexes associated with gene promoters. The discovery of the RA receptor/HDAC complex (7) provides a rationale for combining RAs and HDACIs. The in vitro effects of RAs on neuroblastoma include programmed cell death, growth arrest, and/or terminal differentiation (8 , 9) . Recently, we reported an enhanced inhibitory effect on neuroblastoma cells in culture when HDACIs were combined with RAs (10) .

In this study we examine the effect of the HDACI, CBHA, on neuroblastoma in vivo, both alone and in combination with atRA, using a human neuroblastoma xenograft model in SCID mice. Our data show that CBHA inhibits tumor growth in mice in a dose-dependent fashion. In addition, CBHA and atRA synergistically inhibit tumor growth, rendering lower doses of CBHA effective.

	Materials and Methods

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Cell Culture and Drug Stocks.
The SMS-KCN-69n cell line was provided by Drs. J. Biedler, R. Ross, and B. Spengler (Fordham University, Bronx, NY). Cells were grown in a 1:1 mixture of RPMI 1640 and Ham’s F-12 media with 10% FCS, penicillin, and streptomycin incubated at 37°C and 5% CO₂. Cells were maintained in log-phase growth and harvested with 0.125% trypsin and 0.02% EDTA in HBSS. Stock solutions of CBHA and atRA were prepared in 100% DMSO and stored at -20°C. atRA was protected from light at all times.

Implantation of SMS-KCN-69n Neuroblastoma Xenografts.
SMS-KCN-69n cells were screened in the Memorial Sloan-Kettering Monoclonal Antibody Core Facility to assure freedom from infectious agents. Cells were grown to sufficient numbers in culture, trypsinized as described above, washed three times in PBS, and then resuspended in Matrigel basement membrane matrix (Sigma Chemical Co.) at a concentration of 2 x 10⁷ cells/ml. Female SCID mice 4–6 weeks of age (Taconic) were anesthetized by methoxyflurane inhalation before shaving and skin decontamination with 100% ethanol. Approximately 2 x 10⁶ cells in 0.1 ml of matrix were implanted in the right flank via s.c. injection. Mice were housed in barrier conditions on a 12-h light/dark cycle, with food and water supplied ad libitum. Tumors were allowed 7 days to engraft.

CBHA and atRA Preparation and Administration.
Mice with palpable tumors, all of roughly equivalent size (6.5 ± 0.09 mm x 5.1 ± 0.07 mm, or 91 ± 2.7 mm³), were randomly assigned to one of eight treatment groups, with nine mice in each group. CBHA was administered in a dose of 50 mg/kg, 100 mg/kg, or 200 mg/kg, both alone and in combination with atRA, at a fixed dose of 2.5 mg/kg. One group received atRA alone, and a control group received vehicle (DMSO) alone. Drug stocks were appropriately diluted to keep injection volume at a constant 1 µl/g body weight for all mice. For groups receiving combination treatments, CBHA and atRA were maintained as separate stock solutions in DMSO and mixed daily immediately before injection. Drugs were administered for 21 days via daily i.p. injection. Animals were weighed, with dosages adjusted accordingly, and tumors were measured in two dimensions using calipers three times per week. Tumor volume was calculated using the formula: .

The study concluded on the 21st day of treatment, when the tumor size of the control group necessitated killing. A single mouse from each group was sent alive to a veterinary pathologist at the Research Animal Resource Center of Cornell University Medical College and Memorial Sloan-Kettering Cancer Center for complete tissue necropsy. The remaining animals were killed by CO₂ asphyxiation. Tumors, blood, spleens, livers, and brains were harvested for additional analysis. Tissues were divided, with portions fixed in formalin, frozen in OCT media, frozen in liquid nitrogen, or homogenized for isolation of histones.

Statistical Analysis.
To compare differences between groups with respect to tumor volume over time, a permutation test was used (11) . The null hypothesis for this test is that the growth rates in the two groups are equal. The statistic used to test this hypothesis is the squared differences between mean tumor volumes in each group summed overall time points. This statistic reflects the amount by which the two treatment groups are different with respect to average tumor volume over time: the greater the differences between the trajectories of the average tumor volumes of the two treatment groups, the greater the value of the statistic. All possible permutations of the treatment group affiliations were computed. For each possible permutation, the test statistic was calculated. The P of the permutation test corresponds to the proportion of test statistics from the permutation distribution that was more extreme than the test statistic observed from the experiment.

To assess synergy between CBHA and atRA, a permutation test was again used. Synergistic inhibition of tumor growth is demonstrated when the inhibitory effect of a given dose combination on the average log tumor volume is greater than the sum of the inhibitory effects of the two drugs administered separately. We describe this relationship through the equation

where V is the log tumor volume, a and c represent the doses of atRA and CBHA respectively, and v is the average log tumor volume in the control group.

The nonparametric Wilcoxon rank-sum test was used to determine whether a group’s change in weight from day 1 to day 21 was different from control. ANOVA was used to detect any differences in hematological parameters.

Isolation and Immunoblot Analysis of Histones.
Histones from tumor, liver, and spleen samples (n = 2/group) were isolated as described previously (2) . Acetylated histone H3 was assayed by Western blotting as described previously (4 , 12) .

	Results

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
CBHA Suppresses Growth of Human Neuroblastoma Xenografts Alone and Synergistically with atRA.
The effect of CBHA, both alone and in combination with atRA, in inhibiting the growth of human neuroblastoma in vivo was tested using the N-myc-amplified SMS-KCN-69n cell line xenografted s.c. in SCID mice. Tumor-bearing mice were assigned randomly (n = 9/group) to receive one of three doses of CBHA (50, 100, or 200 mg/kg) alone or with atRA (2.5 mg/kg).⁵ On a per-kilogram basis, the dose of atRA corresponds to a safe dose cited in pediatric pharmacokinetic literature (13) . Drugs were administered by daily i.p. injection. Tumor volumes were measured and compared with controls receiving vehicle or atRA alone (Fig. 1) .

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. s.c. growth of the SMS-KCN-69n neuroblastoma xenograft in SCID mice treated with daily i.p. injections of vehicle (Control), atRA alone, or CBHA (50, 100, or 200 mg/kg) alone or combined with atRA. The dose of atRA was 2.5 mg/kg. Bars, mean tumor volume ± SE. Measurements were obtained every 2–3 days during the 3-week treatment course (total of nine measurements). Tumor volumes for days 1, 6, 11, 16, and 21 are shown. Tumors were implanted 7 days before the start of treatment. Treatment commenced on day 1, when the average tumor volume was 91 ± 2.7 mm3.

The combination of 50 mg/kg CBHA with 2.5 mg/kg atRA led to a 52% reduction of final tumor volume, as compared with control (P = 0.0002; Fig. 1 ). The inhibition of growth by this combination was synergistic, in that its effect was greater than the sum of the effects of the two drugs administered separately (P = 0.01). The addition of atRA to 100 mg/kg CBHA caused greater inhibition of tumor growth, as compared with 100 mg/kg CBHA used as a single agent. Of the animals treated with 100 mg/kg CBHA, the final average tumor volume was reduced an additional 54% in the presence of atRA (P < 0.0001 versus control; Fig. 1 ). The inhibitory effect of 100 mg/kg CBHA combined with atRA was comparable with the maximal effect observed using 200 mg/kg CBHA alone. The enhanced inhibition of growth by this combination approached, but did not reach, significant synergy (P = 0.07). The addition of atRA to the highest dose of CBHA (200 mg/kg) caused no additional tumor growth inhibition; synergy was not detected (P = 0.19).

In addition to the overall growth inhibition noted in treated mice, some animals demonstrated tumor regression, i.e., final tumor size was less than at the outset of treatment. Tumors regressed in one of nine mice treated with 100 mg/kg and two of nine mice treated with 100 mg/kg CBHA combined with atRA. Tumors regressed in three of nine mice treated with 200 mg/kg and in four of nine mice treated with 200 mg/kg CBHA combined with atRA. Tumor regression was not seen in mice treated with 50 mg/kg CBHA either alone or in combination with atRA.

Toxicity of the Higher Doses of CBHA, Alone or in Combination with atRA, was Limited to Mild Weight Loss.
The general condition and weights of the mice were noted throughout the treatment course as a marker of toxicity. Also, serum chemistries, complete blood counts, and full tissue necropsies were performed at the conclusion of treatment. The general appearance of drug-treated mice was indistinguishable from that of vehicle-treated controls, with the exception of the two groups receiving 200 mg/kg CBHA. These animals had disheveled fur and soft stools, suggestive of skin and gastrointestinal toxicity. The addition of atRA seemed to confer little or no greater clinical toxicity than CBHA alone. No animals died as a result of treatment, except for one vehicle-treated animal that sustained a vascular injury during injection.

All drug-treated groups either gained less weight than the vehicle-treated group or had mild weight loss during the treatment period (Table 1) . The differences in weight changes compared with control reached statistical significance in all groups except the group treated with 50 mg/kg CBHA alone. Differences in tumor size may have contributed to the differences in weight, but this could not be quantified because all weights were determined with tumors in situ.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Effect of treatment with CBHA and atRA on hematopoiesis in SCID mice bearing SMS-KCN-69n human neuroblastoma xenografts. Complete blood counts were obtained upon death on the final day of treatment for 3 or 4 animals from each group. P was not significant for each parameter across all groups by ANOVA (see text). WBC count (WBC) is expressed in thousands, hemoglobin (Hgb) as gm/dl, and platelets (Plt) as the value x 105.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Accumulation of acetylated core histone H3 in SMS-KCN-69n neuroblastoma xenografts after administration of CBHA. Tumors were excised from mice on the final day of treatment, 2 h after the final i.p. injection of vehicle (Control) or 50, 100, or 200 mg/kg CBHA (column headings), and histones were isolated. Acetylation of histone H3 was analyzed by Western blotting of histone samples using antibodies to acetylated histone H3 (top panel). Two separate tumors are shown for each dose. Coomassie Blue-stained polyacrylamide gel of the histone samples (bottom panel) controls for protein loading variation.

	Discussion

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

Combination therapies for human tumors using HDACIs and RAs are currently under active investigation (14) . In vitro, the responsiveness of neuroblastoma cells to RAs has been described (8 , 9 , 15) , and clinical evidence now suggests a role for retinoids in high-risk patients as well (16) . Although an earlier trial of 13-cis RA was discouraging (17) , a more recent randomized, controlled trial demonstrated improved outcome after myeloablation and bone marrow transplant in patients who received 13-cis RA versus no additional treatment (16) . The nuclear receptor complex through which RAs exert their biological effects has recently been characterized (7) and was found to contain HDAC. It is possible that HDAC inhibition potentiates the derepression of retinoid responsive genes in the presence of ligand. Indeed, RA-induced differentiation of leukemia cell lines can be enhanced by the addition of an HDACI (14 , 18 , 19) . Remission in a retinoid-resistant APL patient was reported after adding an HDACI to atRA therapy (20) . In neuroblastoma, we have demonstrated in vitro that HDACIs and RAs inhibit the growth of cultured cells in markedly lower concentrations when combined (10) .

Extensive clinical experience with RAs in children has accumulated, making these compounds an available modality for the treatment of refractory neuroblastoma (13) . The results of the current investigation suggest that HDACIs, alone or in combination with retinoids, may be safe and effective agents for the treatment of neuroblastoma disease in children.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by a grant from the I. W. Foundation.

² These authors contributed equally to this work.

³ To whom correspondence should be addressed, at Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-7002; Fax: (212) 717-3053; E-mail: laquaglm{at}mskcc.org

⁴ The abbreviations used are: HDACI, histone deacetylase inhibitor; CBHA m-carboxycinnamic acid bis-hydroxamide; HDAC, histone deacetylase; RA, retinoic acid; SCID, severe combined immunodeficiency; atRA, all-trans retinoic acid.

⁵ L.Z. He, personal communication.

Received 2/ 5/01. Accepted 3/16/01.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Berthold F. Overview: biology of neuroblastoma Pochedly C. eds. . Neuroblastoma: Tumor Biology and Therapy, : 1-30, CRC Press, Inc. Boca Raton, FL 1998.
2. Richon V. M., Emiliani S., Verdin E., Webb Y., Breslow R., Rifkind R. A., Marks P. A. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA, 95: 3003-3007, 1998.[Abstract/Free Full Text]
3. Marks P. A., Richon V. M., Rifkind R. A. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl. Cancer Inst., 92: 1210-1216, 2000.[Abstract/Free Full Text]
4. Glick R. D., Swendeman S. L., Coffey D. C., Rifkind R. A., Marks P. A., Richon V. M., La Quaglia M. P. Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma. Cancer Res., 59: 4392-4399, 1999.[Abstract/Free Full Text]
5. Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev., 12: 599-606, 1998.[Free Full Text]
6. Wolffe A. P., Kurumizaka H. The nucleosome: a powerful regulator of transcription. Prog. Nucleic Acid Res. Mol. Biol., 61: 379-422, 1998.[Medline]
7. Nagy L., Kao H. Y., Chakravarti D., Lin R. J., Hassig C. A., Ayer D. E., Schreiber S. L., Evans R. M. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell, 89: 373-380, 1997.[Medline]
8. Melino G., Thiele C. J., Knight R. A., Piacentini M. Retinoids and the control of growth/death decisions in human neuroblastoma cell lines. J. Neurooncol., 31: 65-83, 1997.[Medline]
9. Sidell N. Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J. Natl. Cancer Inst., 68: 589-596, 1982.
10. Coffey D. C., Kutko M. C., Glick R. D., Swendeman S. L., Butler L., Rifkind R., Marks P. A., Richon V. M., La Quaglia M. P. Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro. Med. Pediatr. Oncol., 35: 577-581, 2000.[Medline]
11. Efron B., Tibshirani R. An Introduction to the Bootstrap Chapman & Hall London 1993.
12. Butler L. M., Agus D. B., Scher H. I., Higgins B., Rose A., Cordon-Cardo C., Thaler H. T., Rifkind R. A., Marks P. A., Richon V. M. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res., 60: 5165-5170, 2000.[Abstract/Free Full Text]
13. Adamson P. C., Reaman G., Finklestein J. Z., Feusner J., Berg S. L., Blaney S. M., O’Brien M., Murphy R. F., Balis F. M. Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-2a in pediatric patients with refractory cancer. J. Clin. Oncol., 15: 3330-3337, 1997.[Abstract/Free Full Text]
14. Yu K. H., Weng L. J., Fu S., Piantadosi S., Gore S. D. Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoic acid. Leukemia, 13: 1258-1265, 1999.[Medline]
15. Meister B., Fink F. M., Hittmair A., Marth C., Widschwendter M. Antiproliferative activity and apoptosis induced by retinoic acid receptor- selectively binding retinoids in neuroblastoma. Anticancer Res., 18: 1777-1786, 1998.[Medline]
16. Matthay K. K., Villablanca J. G., Seeger R. C., Stram D. O., Harris R. E., Ramsay N. K., Swift P., Shimada H., Black C. T., Brodeur G. M., Gerbing R. B., Reynolds C. P. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis- retinoic acid. Children’s Cancer Group. N. Engl. J. Med., 341: 1165-1173, 1999.[Abstract/Free Full Text]
17. Finklestein J. Z., Krailo M. D., Lenarsky C., Ladisch S., Blair G. K., Reynolds C. P., Sitarz A. L., Hammond G. D. 13-cis-retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: report from the Children’s Cancer Study Group. Med. Pediatr. Oncol., 20: 307-311, 1992.[Medline]
18. Breitman T. R., He R. Y. Combinations of retinoic acid with either sodium butyrate, dimethyl sulfoxide, or hexamethylene bisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL60. Cancer Res., 50: 6268-6273, 1990.[Abstract/Free Full Text]
19. Lin R. J., Nagy L., Inoue S., Shao W., Miller W. H., Jr., Evans R. M. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature (Lond.), 391: 811-814, 1998.[Medline]
20. Warrell R. P., Jr., He L. Z., Richon V., Calleja E., Pandolfi P. P. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl. Cancer Inst., 90: 1621-1625, 1998.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. T. Epping, L. A.T. Meijer, J. L. Bos, and R. Bernards UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid Mol. Cancer Res., November 1, 2009; 7(11): 1861 - 1870. [Abstract] [Full Text] [PDF]

				G. Lal and J. S. Bromberg Epigenetic mechanisms of regulation of Foxp3 expression Blood, October 29, 2009; 114(18): 3727 - 3735. [Abstract] [Full Text] [PDF]

				M. Bots and R. W. Johnstone Rational Combinations Using HDAC Inhibitors Clin. Cancer Res., June 15, 2009; 15(12): 3970 - 3977. [Abstract] [Full Text] [PDF]

				C. K. Hahn, K. N. Ross, I. M. Warrington, R. Mazitschek, C. M. Kanegai, R. D. Wright, A. L. Kung, T. R. Golub, and K. Stegmaier Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation PNAS, July 15, 2008; 105(28): 9751 - 9756. [Abstract] [Full Text] [PDF]

				M. T. Epping, L. Wang, J. A. Plumb, M. Lieb, H. Gronemeyer, R. Brown, and R. Bernards A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors PNAS, November 6, 2007; 104(45): 17777 - 17782. [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]

				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]

				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]

				M. Fouladi, W. L. Furman, T. Chin, B. B. Freeman III, L. Dudkin, C. F. Stewart, M. D. Krailo, R. Speights, A. M. Ingle, P. J. Houghton, et al. Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report J. Clin. Oncol., August 1, 2006; 24(22): 3678 - 3685. [Abstract] [Full Text] [PDF]

				R. H. Dashwood, M. C. Myzak, and E. Ho Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis, February 1, 2006; 27(2): 344 - 349. [Abstract] [Full Text] [PDF]

				C. Graham, C. Tucker, J. Creech, E. Favours, C. A. Billups, T. Liu, M. Fouladi, B. B. Freeman III, C. F. Stewart, and P. J. Houghton Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo Clin. Cancer Res., January 1, 2006; 12(1): 223 - 234. [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]

				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. S. Mitsiades, V. Poulaki, C. McMullan, J. Negri, G. Fanourakis, A. Goudopoulou, V. M. Richon, P. A. Marks, and N. Mitsiades Novel Histone Deacetylase Inhibitors in the Treatment of Thyroid Cancer Clin. Cancer Res., May 15, 2005; 11(10): 3958 - 3965. [Abstract] [Full Text] [PDF]

				P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [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] [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]

				R. L. Piekarz, R. W. Robey, Z. Zhan, G. Kayastha, A. Sayah, A. H. Abdeldaim, S. Torrico, and S. E. Bates T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance Blood, June 15, 2004; 103(12): 4636 - 4643. [Abstract] [Full Text] [PDF]

				X. D. Zhang, S. K. Gillespie, J. M. Borrow, and P. Hersey The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells Mol. Cancer Ther., April 1, 2004; 3(4): 425 - 435. [Abstract] [Full Text] [PDF]

				M. C. Kutko, R. D. Glick, L. M. Butler, D. C. Coffey, R. A. Rifkind, P. A. Marks, V. M. Richon, and M. P. LaQuaglia Histone Deacetylase Inhibitors Induce Growth Suppression and Cell Death in Human Rhabdomyosarcoma in Vitro Clin. Cancer Res., November 15, 2003; 9(15): 5749 - 5755. [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]

				L. Catley, E. Weisberg, Y.-T. Tai, P. Atadja, S. Remiszewski, T. Hideshima, N. Mitsiades, R. Shringarpure, R. LeBlanc, D. Chauhan, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma Blood, October 1, 2003; 102(7): 2615 - 2622. [Abstract] [Full Text] [PDF]

				N. Mitsiades, C. S. Mitsiades, P. G. Richardson, C. McMullan, V. Poulaki, G. Fanourakis, R. Schlossman, D. Chauhan, N. C. Munshi, T. Hideshima, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells Blood, May 15, 2003; 101(10): 4055 - 4062. [Abstract] [Full Text] [PDF]

				J. Jaboin, J. Wild, H. Hamidi, C. Khanna, C. J. Kim, R. Robey, S. E. Bates, and C. J. Thiele MS-27-275, an Inhibitor of Histone Deacetylase, Has Marked in Vitro and in Vivo Antitumor Activity against Pediatric Solid Tumors Cancer Res., November 1, 2002; 62(21): 6108 - 6115. [Abstract] [Full Text] [PDF]

				S. Cote, A. Rosenauer, A. Bianchini, K. Seiter, J. Vandewiele, C. Nervi, and W. H. Miller Jr Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells Blood, September 18, 2002; 100(7): 2586 - 2596. [Abstract] [Full Text] [PDF]

				L. M. Butler, X. Zhou, W.-S. Xu, H. I. Scher, R. A. Rifkind, P. A. Marks, and V. M. Richon The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin PNAS, September 3, 2002; 99(18): 11700 - 11705. [Abstract] [Full Text] [PDF]

				G. Sajithlal, H. Huttunen, H. Rauvala, and G. Munch Receptor for Advanced Glycation End Products Plays a More Important Role in Cellular Survival than in Neurite Outgrowth during Retinoic Acid-induced Differentiation of Neuroblastoma Cells J. Biol. Chem., February 22, 2002; 277(9): 6888 - 6897. [Abstract] [Full Text] [PDF]

				M. A. Smith and B. Anderson Where to Next with Retinoids for Cancer Therapy? Clin. Cancer Res., October 1, 2001; 7(10): 2955 - 2957. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Coffey, D. C. Articles by La Quaglia, M. P. Search for Related Content PubMed PubMed Citation Articles by Coffey, D. C. Articles by La Quaglia, M. P.