Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 7, Number 5, October 2006
Contents
New Perspectives in the Treatment of Hematological
Malignancies
Guest Editor: Masahiro Kizaki
Editorial Pp. 313
DNA Hypermethylation of Myeloid Cells, A Novel Therapeutic
Target in MDS and AML Pp. 315-321
C.I. Müller, B. Rüter, H. P. Koeffler
and M. Lübbert
[Abstract]
Induction of Apoptosis via the Modulation
of Reactive Oxygen Species (ROS) Production in the Treatment
of Myeloid Leukemia Pp. 323-329
M. Kizaki, M. Xian, M. Sagawa and Y. Ikeda
[Abstract]
Developing Target Therapy Against Oncogenic Tyrosine
Kinase in Myeloid Maliganacies Pp. 331-337
T. Naoe
[Abstract]
Immunomodulatory Drugs (IMiDs™): A New Treatment
Option for Myelodysplastic Syndromes Pp. 339-342
V. Kale and A.F. List
[Abstract]
Monoclonal Antibodies for the Treatment of Acute
Myeloid Leukemia Pp. 343-369
S.A. Abutalib and M.S. Tallman
[Abstract]
New Tyrosine Kinase Inhibitors in the Treatment
of Chronic Myeloid Leukemia Pp. 371-379
S. Kimura, E. Ashihara and T. Maekawa
[Abstract]
Recent Advances in the Treatment of Multiple Myeloma
Pp. 381-393
H. Yasui, T. Hideshima, P.G. Richardson and K.C. Anderson
[Abstract]
Abstracts
[Back to top]
Editorial
Significant advances in the molecular biology and
therapy of hematological malignancies have been made over
the last decade. The therapeutic approaches to the hematological
malignancies such as acute and chronic leukemias, multiple
myeloma, and malignant lymphoma are basically chemotherapy
to eradicate the malignant cells. However, severe side effects
and complications due to anti-cancer drugs are major problems
in the clinical settings. Moreover, relapsed cases are usually
refractory to chemotherapy and have poor prognosis. These
clinical problems suggest that the current therapeutic strategies
for the hematological malignancies have limitations and novel
effective therapeutic approaches with less toxicity are needed.
In the 1980s, the use of all-trans retinoic acid
(ATRA) for differentiation-inducing therapy in acute promyelocytic
leukemia (APL) has altered the therapeutic strategies of leukemia
and dramatically improved the outcome. In addition, high remission
rates in patients with chronic myeloid leukemia (CML) who
receive imatinib mesylate indicate that molecular-targeted
therapy for hematological malignancies is effective and safe.
At the same time, progress in cellular biology has resulted
in an increased understanding of the molecular genetics of
the diseases and a characterization of the molecular targets
for drug development. However, as for the other molecular-targeted
agents, it is difficult to find a great deal of differences
in the clinical outcome of patients who received standard
therapies over the last decades. Therefore, investigators
have actively sought out new agents with the ability to stimulate
cellular differentiation and induce apoptosis in various cancer
cells. Cellular proliferation, differentiation, and apoptosis
are regulated by a number of extra- and intra-cellular molecules.
These molecules mediate gene transcription either directly
or indirectly by activating various signaling pathways. Molecular
lesions of genes encoding for transcriptional factors are
common oncogenic events in hematological malignancies. The
complexicity of the transcriptional process offers a large
number of substrates for designing therapeutic agents. However,
the success of ATRA in the treatment of APL indicates that
the targeted therapy for transcriptional factors can be highly
effective and safe. As a consequence, the advances of molecular
basis in hematological malignancies have spawned the development
of effective agents such as monoclonal antibodies, specific
enzyme inhibitors, and inhibitors of transcriptional factors.
This special issue attempts to provide a practical introduction
to the attractive and developing field of molecular-targeted
therapy in hematological malignancies.
Masahiro Kizaki
Division of Hematology
Keio University School of Medicine
35 Shinanomachi, Shinjuku-ku, Tokyo
Japan
E-mail: makizaki@sc.itc.keio.ac.jp
[Back to top]
DNA Hypermethylation of Myeloid Cells, A Novel Therapeutic
Target in MDS and AML
C.I. Müller, B. Rüter, H. P. Koeffler
and M. Lübbert
Differential methylation of CpG islands is a regulatory mechanism
for promoter activity of different classes of genes, including
tissue-specific genes. These CpG islands are targets for transformation-associated,
aberrant hypermethylation activity during leukemogenesis.
Therefore the pharmacological reversion of this methylator
phenotype (e.g. by re-activation of tumor suppressor gene
expression) is an important rationale for development of inhibitors
of DNA methyltransferase activity. In vitro, inhibition
of methylation using azanucleosides results in modest differentiation
of transformed myeloid cell lines. In vivo, low doses
of these agents induce DNA demethylation of malignant myeloid
cells. Indeed, the first drug specifically approved for the
treatment of myelodysplastic syndrome (MDS) was the azanucleoside
5-azacytidine (Vidaza®).
The most potent DNA demethylating agent available, 5-aza-2'
deoxycytidine (Decitabine, Dacogen®)
also has recently been approved by the U.S.A. FDA for treatment
of MDS of all subtypes. About 30 % of MDS patients with an
abnormal karyotype have normalization of their karyotype after
receiving the drug. This activity is especially relevant in
patients with high-risk karyotypic abnormalities (complex
karyotype and / or abnormalities of chromosome 7) compared
to patients with intermediate-risk karyotype. Both drugs offer
a novel, non-intensive therapeutic approach, particularly
in the older patient population who due to comorbidities and
/ or reduced performance status are ineligible for aggressive
chemotherapies. Target genes being particularly prone to demethylation
by these drugs in the aberrant cells (e.g. p15/INK4b) are
under active investigation. Future translational and clinical
studies will be aimed at improving the response rate and duration
of response to non-intensive treatment with demethylating
agents, by studying rational drug combinations e.g. with inhibitors
of histone deacetylase activity.
[Back to top]
Induction of Apoptosis via the Modulation
of Reactive Oxygen Species (ROS) Production in the Treatment
of Myeloid Leukemia
M. Kizaki, M. Xian, M. Sagawa and Y. Ikeda
Recent advances in genetic and molecular biology have provided
greater insight into the biology of acute myeloid leukemia
(AML). These investigations have shown that AML is a heterogeneous
disease of biologically different entities. Current therapeutic
approaches to AML are based on chemotherapy, but the side
effects of the drugs used and various complications, including
infections and bleeding, are sometimes fatal. In addition,
responses to therapy and long-term outcome differ depending
on the subentity in question. Therefore, it is essential to
develop new therapeutic strategies such as biology adapted
treatment based on the individual molecular pathogenesis of
AML. Natural compounds appear to be safer than the current
chemotherapeutic drugs, and we have therefore sought new potential
agents among various natural compounds with the ability to
induce the apoptosis of myeloid leukemic cells. Recently,
we found that a highly toxic reactive oxygen species (ROS)
generated via the hydrogen peroxide/myeloperoxidase
[H2O2/MPO/halide] system by natural
compounds induces apoptosis in MPO-positive leukemic cells.
This result is of great interest in establishing novel therapeutic
approaches to AML mediated through ROS-induced apoptosis of
leukemic cells.
[Back to top]
Developing Target Therapy Against Oncogenic Tyrosine
Kinase in Myeloid Maliganacies
T. Naoe
Myeloid malignancies are frequently associated with translocations
and mutations of tyrosine kinase genes. Fusion genes involving
ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs,
and gain-of-function mutations of FLT3, KIT and JAK2
have been detected at various rates in myeloproliferative
disease and acute myeloid leukemia. Furthermore, abnormal
overexpression of tyrosine kinases such as FLT3 has also been
reported. These gene products are constitutively activated
and potentially transform hematopoietic cells by augmentation
of proliferation and enhanced viability. Since the fusion
or mutation of tyrosine kinase is a primary and central event
in chronic myeloproliferative diseases, targeting the kinase
activity has been thought to be an ideal intervention to treat
these diseases. The clinical success of imatinib for chronic
myeloid leukemia has made this idea a reality, and has accelerated
the development of new tyrosine kinase inhibitors (TKIs).
Challenging studies with TKIs have also been reported for
acute myeloid leukemia. This review will focus on recent trials
of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3
and KIT) in myeloid malignancies.
[Back to top]
Immunomodulatory Drugs (IMiDs™): A New Treatment
Option for Myelodysplastic Syndromes
V. Kale and A.F. List
The IMiDs™
represent a new proprietary class of thalidomide analogues
that possess greater potency and less toxicity than the parent
compound. As a group, these agents share the pharmacologic
property of modulating cellular response to ligand activation,
the precise biologic effect of which is cell lineage and stimulant-dependent.
Lenalidomide (CC-5013; Revlimid™),
a second generation IMiD, has shown significant erythropoietic
activity in patients with lower risk MDS that have failed
or are not candidates for recombinant erythropoietin treatment.
Unlike cytokine therapy, lenalidomide suppresses select MDS
clones and enhances erythropoietin receptor signaling to restore
erythropoiesis. Activity is greatest in patients with interstitial
deletions involving chromosome 5q31.1. A multicenter phase
II study reported a 76 % overall transfusion response rate
in transfusion-dependent patients with deletion 5q, with 67
% achieving transfusion independence after a median interval
of 4.6 weeks of treatment. Cytogenetic responses were observed
in 73% of patients with complete cytogenetic remission in
45% patients. Both transfusion response and cytogenetic response
frequency were independent of karyotype complexity, raising
excitement that this new treatment strategy might favorably
alter the natural history of disease in higher risk patients
with deletion 5q. Lenalidomide was approved by the U.S. Food
and Drug Administration on December 27, 2005, for the treatment
of IPSS Low and intermediate-1 risk MDS patients with del(5q)
abnormality. A phase III Intergroup trial (ECOG 2905) will
test the capacity to potentiate erythropoietin response by
comparing response to lenalidomide monotherapy to the combination
of darbepoetin and lenalidomide in non-deletion 5q MDS patients.
[Back to top]
Monoclonal Antibodies for the Treatment of Acute Myeloid
Leukemia
S.A. Abutalib and M.S. Tallman
Currently, patients with acute myeloid leukemia (AML) are
treated with cytotoxic chemotherapy and hematopoietic stem
cell transplantation (HSCT). With this approach, the majority
of patients still die of their disease because of both treatment-related
mortality and relapse. Recently, monoclonal antibodies and
immunoconjugates have been developed which potentially may
increase the efficacy of treatment and decrease morbidity
and mortality by specifically targeting the malignant cell.
Unconjugated monoclonal antibodies have shown only moderate
activity. A second, more effective, approach involves an-tibody
conjugation with radioactive particles or chemotherapeutic
agents, such as, immunotoxins, targeted delivery of cell killing.
The antigens CD33, CD45, and CD66, are three antigens to which
monoclonal antibodies have been directed. Most experience
has been with gemtuzumab ozogamicin (Mylotarg) which is an
immunoconjugate of an anti-CD33 anti-body chemically linked
to a potent cytotoxic agent, calicheamicin. Gemtuzumab ozogamicin
appears to be particularly active in patients with acute promyelocytic
leukemia, possibly related to the high expression of the CD33
antigen on the cell surface. Although gemtuzumab ozogamicin
has activity as a single agent, the most promising result
may be seen when this agent is combined with conventional
cytotoxic chemotherapy. Preliminary studies have suggested
a high complete remission rate and randomized clinical trials
are underway. A unique potential toxicity has been identified,
namely venoocclusive disease or sinusoidal obstructive syndrome
which may be problematic among patients who subsequently undergo
HSCT. An additional strategy includes radiolabeled monoclonal
antibodies to intensify the conditioning regimen prior to
HSCT. The most promising results have been obtained with radiolabeled
anti-CD45 antibodies.
[Back to top]
New Tyrosine Kinase Inhibitors in the Treatment of
Chronic Myeloid Leukemia
S. Kimura, E. Ashihara and T. Maekawa
Imatinib mesylate, Abl tyrosine kinase inhibitor, has improved
the treatment of Bcr-Abl-positive leukemia such as chronic
myeloid leukemia (CML) and Philadelphia chromosome positive
acute lymphoblastic leukemia (Ph+ALL).
However, resistance is often reported in patients with advanced-stage
disease. Several novel tyrosine kinase inhibitors, which have
been developed to override imatinib resistance mechanisms
such as overexpression of Bcr-Abl and point mutations within
the Abl kinase domain, are currently competing. Inhibitors
of Abl tyrosine kinase are divided into two main groups, namely,
ATP-competitive and ATP non-competitive inhibitors. Moreover,
ATP-competitive inhibitors are fall into two subclasses, i.e.
the Src/Abl inhibitors, and 2-phenylaminopyrimidin-based compounds.
Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326
are classified as Src/Abl inhibitors while AMN107 and NS-187
(INNO-406) belong to the latter subclass of inhibitors. Among
these agents, clinical studies on dasatinib and AMN107 had
started earlier than the others and favorable results are
accumulating. Clinical studies of other compounds including
NS-187 (INNO-406) will be performed in rapid succession. Because
of its strong affinity, most ATP competitive inhibitors may
be effective against imatinib-resistant patients. However,
to date, an ATP-competitive inhibitor that can inhibit the
phosphorylation of T315I Bcr-Abl has not yet been developed.
To address this problem, ATP non-competitive inhibitors such
as ON012380, Aurora kinase inhibitor VX-680 and p38 MAP kinase
inhibitor BIRB-796 have been developed. It may be necessary
for the improvement of CML and Ph+ALL
treatment to be taken into consideration of the combination
therapy with novel ATP-competitive inhibitors and these agents.
[Back to top]
Recent Advances in the Treatment of Multiple Myeloma
H. Yasui, T. Hideshima, P.G. Richardson and K.C. Anderson
Multiple Myeloma (MM) remains an incurable plasma cell malignancy
in the bone marrow (BM) despite conventional therapies as
well as high-dose therapies with stem cell support. Therefore
novel biologically-based therapeutic approaches are required.
Recently, intensive laboratory and preclinical studies have
identified and validated therapeutic molecular targets in
MM. In particular, recognition of the biologic significance
of the BM microenvironment in MM pathogenesis and as a potential
target for novel therapeutics has derived several promising
approaches. Novel FDA approved agents including thalidomide/thalomid®,
its immunomodulatory derivatives lenalidomide/Revlimid®,
and proteasome inhibitor bortezomib/Velcade®
are directed at molecular targets not only in MM cells but
also in its BM milieu, and have already achieved promising
results in clinical studies. Here we discuss the mechanisms
of action of these novel drugs and their clinical application,
alone or combined with conventional or novel drugs.
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