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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2865-2868
BRIEF REPORT
Inhibitor of histone deacetylation, depsipeptide (FR901228), in
the treatment of peripheral and cutaneous T-cell lymphoma: a case
report
Richard L. Piekarz,
Rob Robey,
Victor Sandor,
Susan Bakke,
Wyndham H. Wilson,
Laila Dahmoush,
Douglas M. Kingma,
Maria L. Turner,
Rosemary Altemus, and
Susan E. Bates
From the Medicine Branch, the Laboratory of Pathology,
the Dermatology Branch, and the Radiation Oncology Branch of the Center
for Cancer Research, National Cancer Institute, National Institutes of
Health, Bethesda, MD.
 |
Abstract |
Depsipeptide, FR901228, has demonstrated potent in vitro and in
vivo cytotoxic activity against murine and human tumor cell lines. In
the laboratory, it has been shown to be a histone deacetylase (HDAC)
inhibitor. In a phase I trial of depsipeptide conducted at the National
Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a
partial response, and 1 patient with peripheral T-cell lymphoma,
unspecified, had a complete response. Sézary cells isolated from
patients after treatment had increased histone acetylation. These
results suggest that inhibition of HDAC is a novel and potentially
effective therapy for patients with T-cell lymphoma.
(Blood. 2001;98:2865-2868)
© 2001 by The American Society of Hematology.
| |
Introduction |
Postthymic T-cell lymphomas represent about
10% of all non-Hodgkin lymphomas. Peripheral T-cell lymphomas,
unspecified, compose one subset. Patients with peripheral
T-cell lymphoma may have a durable remission after they achieve a
complete response with standard chemotherapy, with an overall survival
rate of 25% at 5 years.1 However, most patients
experience relapse and have a poor response to further
treatment.2 Cutaneous T-cell lymphoma (CTCL) is another
subset of postthymic lymphomas and accounts for approximately half of
all lymphomas that arise in the skin. Among various forms of CTCLs,
mycosis fungoides and the Sézary syndrome are the most
common.3,4 Although patients with advanced stage CTCL
respond to various forms of cytotoxic or biological therapies, these
responses are typically short lived.5 In this report, we
describe several patients with postthymic T-cell lymphoma that were
treated on a phase I trial of a histone deacetylase (HDAC) inhibitor, depsipeptide.
Depsipeptide, FR901228, has been isolated from
Chromobacterium violaceum and has demonstrated potent
antitumor activity in vitro and against both human tumor xenografts and
murine tumors in vivo.6,7 These include the human A549
lung adenocarcinoma, MCF-7 and ZR-75-1 breast adenocarcinoma, and LOX
IMVI melanoma cell lines.6,7 Depsipeptide shows a lack of
cross-resistance with several commonly used cytotoxic agents; however,
it has been identified as a P-glycoprotein (Pgp)
substrate.8 Depsipeptide is a member of a novel class of
antineoplastic agents, the HDAC inhibitors (HDIs).9 HDIs
have been shown to induce differentiation, decrease cell proliferation,
and induce cell death. HDIs increase acetylation of histones, as well
as other nuclear factors, modulating the expression of genes that play
a role in the control of cell growth and
differentiation.10
| |
Study design |
A phase I study of depsipeptide was conducted in the
Medicine Branch, National Cancer Institute (NCI); details of the trial are being reported separately (V.S. et al, manuscript submitted). Four
patients with T-cell lymphoma were enrolled and treated at the 12.7 or
17.8 mg/m2 dose level. The drug was administered by a
4-hour infusion on days 1 and 5 of a 21-day cycle. Responses were
scored according to the World Health Organization
criteria11 with skin responses scored as described by
Zinzani et al.12 Toxicities were graded according to
the NCI Common Toxicity Criteria. The major observed toxicities
were fatigue, nausea, vomiting, granulocytopenia, thrombocytopenia, and
hypocalcemia (V.S. et al, manuscript submitted).
Histone acetylation assays were performed on cytospins from patients'
peripheral mononuclear cells. Slides were fixed with 95% ethanol/5%
acetic acid, washed twice with phosphate-buffered saline (PBS), blocked
with 8% bovine serum albumin (BSA), and then washed with PBS. The
slides were then incubated overnight at 4°C with anti-acetyl histone
H3 antibody (Upstate Biotechnology, Lake Placid, NY) diluted 1:200 in
2% BSA. After 2 washes, the slides were stained with horse
anti-rabbit fluorescein isothiocyanate-conjugated secondary antibody
(Vector Laboratories, Burlingame, CA), for 1 hour. After 3 washes, the
slides were counterstained with 4' 6-diamidino-2-phenylindole-2HCl
containing antifade compound (Vector Laboratories).
Fine-needle aspirates were performed by a cytopathologist using a
23- or 25-gauge needle, with on-site evaluation of Diff-Quick-stained smears (Dade Diagnostics, Aguada, PR). The remainder of the
sample was rinsed with RPMI 1640 (Gibco BRL, Grand Island, NY) and
processed as Diff-Quick-stained cytospins.
| |
Results |
Patients 1 and 2 are men 63 and 53 years old,
respectively, both diagnosed with Sézary syndrome.
Neither patient responded to previous therapies, which included either
cyclophosphamide, doxorubicin, vincristine, and prednisone or
clyclophosphamide, vincristine, and prednisone. They were symptomatic
with itching, and their physical examinations were significant for
erythema and scaling of their trunks and extremities. Both had a white blood count (WBC) exceeding 60 × 109/L
(60 000/µL). Flow cytometry identified a clonal population of T-helper lymphocytes in the peripheral blood. Computed tomography (CT) scans demonstrated enlarged lymph nodes. Following treatment with
depsipeptide, there was a rapid decrease of circulating Sézary cells and improvement of skin erythema and edema. In addition, there
was an increase in histone acetylation in peripheral mononuclear cells, which were, in these patients, composed predominantly of Sézary cells (Figure 1).
Patient 1 was removed from the study after 4 cycles after developing
multiple subcutaneous abscesses of methicillin-resistant
Staphylococcus aureus. Patient 2 was removed from study
after 5 cycles for pruritis and erythema that persisted despite
therapy.
View larger version (45K):
[in this window]
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| Figure 1.
Effect of treatment on Sézary cell count, histone
acetylation, and lymphoma cells.
The graphs represent the WBC, absolute granulocyte count, and
Sézary cell counts of patient 1 (panel A) and 2 (panel B) in
response to treatment with depsipeptide. The x-axis indicates the days
of the cycle; the arrows in the chart indicate the days that
depsipeptide was administered. Below are peripheral mononuclear cells
following fluorescent labeling with anti-acetyl histone H3.
The majority of the cells are Sézary cells taken from the
patients prior to infusion of depsipeptide, at the completion of the
4-hour infusion and (in panel B) at 24 hours after initiation of the
infusion. In panel C, the section on the left was from a fine-needle
aspiration biopsy prior to the initiation of therapy and demonstrates
atypical lymphocytes with enlarged hyperchromatic nuclei and scant deep
basophilic cytoplasm (Diff-Quick × 400). The section on the right was
obtained after administration of the second dose of the first cycle and
has cells with vacuolization of cytoplasm and fragmentation of nuclei
(Diff-Quick × 400).
|
|
Patient 3 is a 78-year-old man who presented with tumor-stage
CTCL. He was symptomatic with mild generalized pruritus, and his
physical examination was notable for hundreds of tumors without the
sparing of any skin areas. These lesions had developed within the
previous 4 months and were not amenable to treatment with total-skin
electron beam therapy or other topical therapies. After administration
of the second dose of depsipeptide of the first cycle, fine-needle
aspirations of 2 lesions were performed. A cytological examination
showed many cells with cytoplasmic vacuolization and nuclear
fragmentation, suggesting that a significant population of the tumor
cells were affected by treatment (Figure 1C). There was clearing of
almost all tumors after 6 cycles of treatment (Figure
2A). Five lesions that had initially
responded to treatment eventually progressed through therapy and were
treated with radiation.
View larger version (64K):
[in this window]
[in a new window]
| Figure 2.
Clinical effects of
depsipeptide.
Photographs of patient 3 (panel A) and photographs and abdominal CT
sections of patient 4 (panel B) before (left) and after (right)
treatment with depsipeptide. These demonstrate a response of the
cutaneous tumors on the face and torso of patient 3 and of the
erythematous plaques on the legs, and retroperitoneal lymphadenopathy
of patient 4 after treatment with depsipeptide.
|
|
Patient 4 is a 53-year-old man with peripheral T-cell lymphoma,
unspecified. Physical examination demonstrated erythemous plaques of
the skin with nodules over the elbows, buttocks, and thighs and a large
3- to 4-cm mass over the plantar surface of the left foot. There was no
bone marrow involvement. CT scan of the chest, abdomen, and
pelvis showed mediastinal, retrocrural, axillary, retroperitoneal,
pelvic, and inguinal adenopathy. After one cycle of etoposide,
prednisone, vincristine, cyclophosphamide, and doxorubicin
chemotherapy, the patient experienced progression of his subcutaneous
nodules and erythema and was enrolled on the phase I depsipeptide
study. After initiation of depsipeptide, there was clearing of his
cutaneous lesions, skin nodules, and lymphadenopathy on CT scan (Figure
2B). He was declared to be in complete remission (CR) after the eighth cycle.
| |
Discussion |
Depsipeptide is a member of the new class of antineoplastic
agents, the HDIs. Depsipeptide, like other HDIs, has been shown to induce cell cycle arrest in both G1 and G2/M
phases and to induce apoptosis in several cell lines.13
Depsipeptide induces increased expression of p21, cyclin E, decreased
expression of cyclin D1, and hypophosporylation of Rb.14
Other molecular changes include a decreased expression of c-myc in
fibroblasts13 and in T-cell hybridomas.15
Other changes in the cellular milieu remain to be elucidated.
The case reports presented here suggest that depsipeptide, and
potentially other HDIs, may be effective in T-cell lymphomas. Subsequent to these clinical observations, similar findings were also
reported in laboratory models.16 Recent studies have shown that HDIs have activity against acute myeloid leukemia cell
lines,17,18 an observation that may be related to
chromosomal translocations that result in the synthesis of chimeric
proteins with altered HDAC or histone acetyltransferase
activity.18 Given the observed responses to depsipeptide,
it seems plausible to hypothesize that alterations in HDACs or histone
acetyltransferases may be involved in the pathogenesis of T-cell lymphomas.
On the basis of the observed responses, a phase II study testing
depsipeptide in patients with cutaneous T-cell or peripheral T-cell
lymphomas has been initiated. Since the patients with CTCL had some
benefit from depsipeptide but did not achieve a CR, it will be
important to identify agents that can be effectively combined with
depsipeptide. Among the agents that it would be reasonable to consider
are cytotoxic chemotherapeutic agents, Pgp inhibitors, retinoids, or
interleukin-2 (IL-2) receptor-targeting agents. The tumors from
patients 1, 3, and 4 were CD25 , a marker for the
 -subunit of the IL-2 receptor. The circulating Sézary cells of
patients 1 and 2 were CD25 at the start of therapy, but
were CD25+ after several cycles of treatment and, in the
case of patient 1, after the second dose of the first cycle (data not
shown). It is noteworthy that a recent report demonstrated that
Sézary cells treated with the HDI arginine butyrate had increased
expression of the IL-2 receptor and increased sensitivity to IL-2
receptor-targeted therapy.19
In conclusion, this is the first report that demonstrates a clinical
response to an HDI in a specific tumor type. In light of the poor
therapy existing for patients with T-cell lymphoma, depsipeptide
represents a promising new agent in the treatment of these patients.
| |
Footnotes |
Submitted March 19, 2001; accepted June 28, 2001.
Supported in part by research funding from the Fujisawa Pharmaceutical Company.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Richard L. Piekarz, 9000 Rockville Pike, Bldg 10, Rm 12n226, Bethesda, MD 20892; e-mail: rpiekarz{at}nih.gov.
| |
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R. V. Kumar, P. C. Mu, V. Ravikumar, and T. Devaki
Inhibitory Effects of Histone Deacetylase Inhibitor Depsipeptide on Benzo(a)pyrene- and Cyclophosphamide-Induced Genotoxicity in Swiss Albino Mice
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[Abstract]
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S. E. Bates, D. R. Rosing, T. Fojo, and R. L. Piekarz
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M. H. Shah, P. Binkley, K. Chan, J. Xiao, D. Arbogast, M. Collamore, Y. Farra, D. Young, and M. Grever
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[Abstract]
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R. L. Piekarz, A. R. Frye, J. J. Wright, S. M. Steinberg, D. J. Liewehr, D. R. Rosing, V. Sachdev, T. Fojo, and S. E. Bates
Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma.
Clin. Cancer Res.,
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[Abstract]
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[Abstract]
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R. W. Robey, Z. Zhan, R. L. Piekarz, G. L. Kayastha, T. Fojo, and S. E. Bates
Increased MDR1 Expression in Normal and Malignant Peripheral Blood Mononuclear Cells Obtained from Patients Receiving Depsipeptide (FR901228, FK228, NSC630176)
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M. A. Rizvi, A. M. Evens, M. S. Tallman, B. P. Nelson, and S. T. Rosen
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N. Gao, M. Rahmani, X. Shi, P. Dent, and S. Grant
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M. R. Acharya, A. Sparreboom, J. Venitz, and W. D. Figg
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Mol. Pharmacol.,
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O. A. O'Connor
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R. van Doorn, W. H. Zoutman, R. Dijkman, R. X. de Menezes, S. Commandeur, A. A. Mulder, P. A. van der Velden, M. H. Vermeer, R. Willemze, P. S. Yan, et al.
Epigenetic Profiling of Cutaneous T-Cell Lymphoma: Promoter Hypermethylation of Multiple Tumor Suppressor Genes Including BCL7a, PTPRG, and p73
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Y. Xiong, S. C. Dowdy, K. C. Podratz, F. Jin, J. R. Attewell, N. L. Eberhardt, and S.-W. Jiang
Histone Deacetylase Inhibitors Decrease DNA Methyltransferase-3B Messenger RNA Stability and Down-regulate De novo DNA Methyltransferase Activity in Human Endometrial Cells
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J. C. Byrd, G. Marcucci, M. R. Parthun, J. J. Xiao, R. B. Klisovic, M. Moran, T. S. Lin, S. Liu, A. R. Sklenar, M. E. Davis, et al.
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P. M. Das and R. Singal
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S. Doi, H. Soda, M. Oka, J. Tsurutani, T. Kitazaki, Y. Nakamura, M. Fukuda, Y. Yamada, S. Kamihira, and S. Kohno
The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells
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S. Roychowdhury, R. A. Baiocchi, S. Vourganti, D. Bhatt, B. W. Blaser, A. G. Freud, J. Chou, C.-S. Chen, J. J. Xiao, M. Parthun, et al.
Selective Efficacy of Depsipeptide in a Xenograft Model of Epstein-Barr Virus-Positive Lymphoproliferative Disorder
J Natl Cancer Inst,
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K. J. Savage, M. Chhanabhai, R. D. Gascoyne, and J. M. Connors
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L. A. Wolfraim, T. M. Fernandez, M. Mamura, W. L. Fuller, R. Kumar, D. E. Cole, S. Byfield, A. Felici, K. C. Flanders, T. M. Walz, et al.
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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,
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[Abstract]
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M. Adachi, Y. Zhang, X. Zhao, T. Minami, R. Kawamura, Y. Hinoda, and K. Imai
Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells
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Apoptosis Induced by the Histone Deacetylase Inhibitor FR901228 in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells
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[Abstract]
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M. Rahmani, C. Yu, Y. Dai, E. Reese, W. Ahmed, P. Dent, and S. Grant
Coadministration of the Heat Shock Protein 90 Antagonist 17-Allylamino- 17-demethoxygeldanamycin with Suberoylanilide Hydroxamic Acid or Sodium Butyrate Synergistically Induces Apoptosis in Human Leukemia Cells
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M. E. Goldsmith, M. Kitazono, P. Fok, T. Aikou, S. Bates, and T. Fojo
The Histone Deacetylase Inhibitor FK228 Preferentially Enhances Adenovirus Transgene Expression in Malignant Cells
Clin. Cancer Res.,
November 1, 2003;
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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
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D. D. Klisovic, S. E. Katz, D. Effron, M. I. Klisovic, J. Wickham, M. R. Parthun, M. Guimond, and G. Marcucci
Depsipeptide (FR901228) Inhibits Proliferation and Induces Apoptosis in Primary and Metastatic Human Uveal Melanoma Cell Lines
Invest. Ophthalmol. Vis. Sci.,
June 1, 2003;
44(6):
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[Abstract]
[Full Text]
[PDF]
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Md. M. Rahman, A. Kukita, T. Kukita, T. Shobuike, T. Nakamura, and O. Kohashi
Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages
Blood,
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G. D. Kao, W. G. McKenna, M. G. Guenther, R. J. Muschel, M. A. Lazar, and T. J. Yen
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S. Skov, K. Rieneck, L. F. Bovin, K. Skak, S. Tomra, B. K. Michelsen, and N. Odum
Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal pathway essential for CD154 expression
Blood,
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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,
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Cancer Res.,
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H. Kamitani, S. Taniura, K. Watanabe, M. Sakamoto, T. Watanabe, and T. Eling
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Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment : Commentary re: V. Sandor et al., Phase I Trial of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228, NSC 630176), in Patients with Refractory Neoplasms. Clin. Cancer Res., 8: 718-728, 2002.
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Top
Abstract
Introduction
