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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 7, 2006
Contents
New Therapies in Prostate Cancer:Controlling Metastatic
Disease and Preventing Oncogenesis
Executive Editor: B.F. Schwartz
Antithrombotic Drug Design
Executive Editor: Hiroyuki Matsuno
Editorial Pp. 773
Inhibitors of 5α-Reductase
in the Treatment of Benign Prostatic Hyperplasia Pp.
775-783
T.H. Tarter and E.D. Vaughan, Jr.
[Abstract]
Treatment of PSA only Recurrence of Prostate Cancer
After Prior Local Therapy Pp. 785-798
J.W. Moul
[Abstract]
Controversies of Androgen Ablation Therapy for Metastatic
Prostate Cancer Pp. 799-805
S.S. Wilson and E.D. Crawford
[Abstract]
Immunotherapy for Prostate Cancer Pp. 807-817
R.J. Karnes, C.M. Whelan and E.D. Kwon
[Abstract]
Chemotherapy for Prostate Cancer Pp. 819-837
S.W. Dyrstad, P. Shah and K. Rao
[Abstract]
Antithrombotic Drug Design
Executive Editor: Hiroyuki Matsuno
Editorial Pp. 839
α2-Antiplasmin
on Cardiovascular Diseases Pp. 841-857
H. Matsuno
[Abstract]
Development of New Fibrinolytic Agents
Pp. 849-857
S. Ueshima and O. Matsuo
[Abstract]
The Platelet ATP and ADP Receptors Pp. 859-875
C. Oury, E. Toth-Zsamboki, J. Vermylen and M.F. Hoylaerts
[Abstract]
Novel Ideas of Gene Therapy for Atheroscrelosis: Modulation
of Cellular Signal Transduction of TGF-β
Family Pp. 877-886
A. Ishisaki and H. Matsuno
[Abstract]
The Possibility of Novel Antiplatelet Peptides: The Physiological
Effects of Low Molecular Weight HSPs on Platelets Pp.
887-892
Y. Kanno and H. Matsuno
[Abstract]
Abstracts
[Back
to top]
Editorial
Prostate cancer continues to be a significant
public health concern throughout the world. It remains the
most common male cancer after skin cancer and leads to the
second most number of male cancer deaths behind lung cancer.
Almost 85% of all prostate cancers are diagnosed in the local
or regional stages and the five-year relative survival rate
for these men approaches 100%. Incidence rates over the last
30 years are only slightly higher. The introduction of prostate
specific antigen (PSA) produced a tremendous rise in diagnosed
cases in the early 1990’s but was followed by a leveling
off to an incidence not too different than the mid 1970’s.
Many patients however, are able to live longer with their
disease thanks to treatment of metastatic disease. Breakthroughs
in earlier diagnosis, aggressive early treatment, better adjuvant
therapy for primary treatment failures and successful treatment
for metastatic disease has greatly improved the quantity and
quality of lives for prostate cancer patients. Also, tremendous
breakthroughs in understanding the physiology of prostate
endocrinology, mainly in the form of five alpha-reductase,
have contributed to the diagnosis and management of prostate
disease.
The current issue of Current Pharmaceutical Design presents
an excellent overview and current work on timely prostate
cancer topics. Although not a lot of progress has been made
on prostate cancer prevention, promising new areas of interest
have surfaced. Five alpha reductase inhibitors successfully
inhibit prostate cell proliferation and in preliminary studies
may be prevent prostate cancer. Their effects on benign prostate
disease are well known. Drs. Tarter and Vaughan [1] provide
an excellent review of these agents, their mechanisms of action
and their potential roles in prostate cancer prevention.
The advent of PSA has greatly assisted the medical community
in diagnosing, treating and following prostate cancer. PSA
elevation after definitive local therapy continues to be challenging
to patient and physician alike. Dr. Moul [2] provides a comprehensive
review of various treatment options for this clinical entity
based on his own experience and a review of the world literature.
Successful treatment of metastatic prostate cancer has prolonged
the lives of millions of men and improved the quality of their
lives. Multiple regimens and treatment options exist for these
patients but not without controversy. A thorough review of
this topic is provided by Drs. Wilson and Crawford [3].
Finally, the last two papers represent some of the most exciting
areas in all of cancer research: immunotherapy and chemotherapy.
Traditionally, these two modalities have been ineffective
in the treatment of prostate cancer. Dr. Karnes and his group
[4] provide the current status and future directions of immunotherpy
for prostate cancer while Dr. Malkowicz [5] discusses current
breakthroughs and the future promises of chemotherapy in the
treatment of prostate cancer.
It is with the assistance of these authors that scientific
progress is made in the treatment of a disease that kills
roughly 100,000 men worldwide per year. They are to be congratulated
for their work and I thank them sincerely for their contributions.
References
[1] Tarter TH, Vaughan Jr, ED. Inhibitors of 5?-Reductase
in the Treatment of Benign Prostatic Hyperplasia. Curr Pharm
Design 2006; 12(7): 775-783.
[2] Moul JW. Treatment of PSA only Recurrence of Prostate
Cancer After Prior Local Therapy. Curr Pharm Design 2006;
12(7): 785-798.
[3] Wilson SS, Crawford ED. Controversies of Androgen Ablation
Therapy for Metastatic Prostate Cancer. Curr Pharm Design
2006; 12(7): 799-805.
[4] Karnes RJ, Whelan CM, Kwon ED. Immunotherapy for Prostate
Cancer. Curr Pharm Design 2006; 12(7): 807-817.
[5] Dyrstad SW, Shah P, Rao K. Chemotherapy for Prostate
Cancer. Curr Pharm Design 2006; 12(7): 819-837.
B.F. Schwartz
Associate Professor of Urology
Director, Center for Laparoscopy and Endourology
Southern Illinois University
P.O. Box 19665
Springfield, IL 62794-9665
USA
Tel: (217) 545-7390
Fax: (217) 545-7305
E-mail: bschwartz@siumed.edu
[Back to top]
Inhibitors of 5α-Reductase
in the Treatment of Benign Prostatic Hyperplasia
T.H. Tarter and E.D. Vaughan, Jr.
The description of 5α-reductase
deficiency in male pseudohermaphroditism, characterization
of type-1 and type-2 isoenzymes of 5α-reductase,
and development of 4-aza steroid competitive inhibitors of
5α-reductase
were milestones in the development of 5α-reductase
inhibitors, a class of drugs approved for the treatment of
symptomatic benign prostatic hyperplasia (BPH). Stromal and
epithelial hyperplasia in the region of the prostate that
surrounds the urethra begins in the fourth decade of life
and by the sixth decade, the prevalence is 50%. Benign prostatic
hyperplasia is a frequent cause of lower urinary tract symptoms,
urinary tract infection, and acute urinary retention requiring
surgical intervention. Medical options for treatment of symptomatic
BPH include 1) the 5α-reductase
inhibitors finasteride and dutasteride, 2) the α1-adrenergic
antagonists doxazocin, terazosin, tamsulosin, and alfuzosin,
and 3) the combination of a 5α-reductase
inhibitor and a α1-adrenergic
antagonist. By inhibiting the production of dihydrotestosterone
(DHT) locally within the prostate gland, 5α-reductase
inhibitors have the effect of reducing prostate volume, improving
lower urinary tract symptoms, increasing peak urinary flow,
and decreasing the risk of acute urinary retention and need
for surgical intervention. Alpha-1 adrenergic antagonists
relax the smooth muscle of the bladder neck and prostate,
thereby decreasing the resistance to urine flow and increasing
peak urinary flow and improving lower urinary tract symptoms.
The α1-adrenergic
antagonists are effective in the short-term, and reduce clinical
progression of BPH, but do not reduce the long-term risk of
urinary retention or need for surgical intervention. The 5α-reductase
inhibitors are effective in the long-term, especially in men
with large prostates, and reduce the clinical progression
of BPH, and further reduce the long-term risk of urinary retention
and need for surgical intervention. The combination of a 5α-reductase
inhibitor and a α1-adrenergic
antagonist significantly reduces the clinical progression
of BPH over either drug class alone.
[Back to top]
Treatment of PSA only Recurrence of Prostate Cancer
After Prior Local Therapy
J.W. Moul
Prostate cancer recurrence (after prior local treatment)
that is detectable only by a rise in serum prostate specific
antigen (PSA) level is a very common problem facing clinicians.
Given that the majority of contemporary era men with PSA-only
or biochemical recurrence are relatively young and otherwise
healthy, treatment requires approaches that both improve clinical
outcomes and preserve quality of life. Treatment is in one
of two broad categories, additional local therapies, termed
“salvage” local therapy and systemic therapies.
For radical prostatectomy patients, salvage external beam
radiotherapy to the prostate bed is commonly employed, being
reserved for early biochemical recurrence in men with low
risk at distant metastases. For primary radiation patients,
salvage radical prostatectomy or cryotherapy can similarly
be used for those men felt not to harbor distant metastases.
Systemic therapy generally involves hormonal ther-apy. Traditional
hormonal therapy (orchiectomy, luteinizing hormone-releasing
hormone agonists or maximum androgen blockade) is the current
mainstay of systemic treatment for biochemical recurrence,
although non-traditional approaches, such as antiandrogen
monotherapy, are increasingly being used. There is a critical
need for new pharmaceutical agents to treat this growing stage
of prostate cancer. However, it has been difficult to demonstrate
efficacy due to the long natu-ral history until death and
the survival endpoint currently required by the U.S. Food
and Drug Administration. New data show that PSA Doubling time
(PSA-DT) during PSA recurrence may be a valid surrogate for
death from the disease and may be used to accelerate drug
approval. This monograph will attempt to provide a complete
balanced discussion of the evaluation and treatment of biochemical
recurrence of prostate cancer after prior primary local therapy.
[Back to top]
Controversies of Androgen Ablation Therapy
for Metastatic Prostate Cancer
S.S. Wilson and E.D. Crawford
Ever since Huggins and Hodges won a Nobel Prize in 1966
for their work describing the relationship between testosterone
and prostate cancer, androgen deprivation has continued to
be an important component in the treatment of prostate cancer.
Refinements in the therapy have occurred in the past 50 years,
yet controversies still exist. This review details the controversies
and advances in androgen deprivation for prostate cancer including:
neoadjuvant androgen deprivation, combined androgen blockade,
early versus late androgen deprivation treatment, intermittent
versus continuous androgen deprivation monotherapy, anti-androgen
monotherapy, anti-androgen and 5-alpha reductase inhibitor
combinations, androgen deprivation with periodic intravenous
bisphosphonate infusions, and androgen deprivation in conjunction
with chemotherapy.
[Back to top]
Immunotherapy for Prostate Cancer
R.J. Karnes, C.M. Whelan and E.D. Kwon
The absence of curative therapies for advanced or recurrent
forms of prostate cancer has prompted a vigorous search for
novel treatment strategies. Immunotherapy encompasses one
particularly promising systemic approach to treat prostate
cancer. Immune-based strategies to treat prostate cancer have
recently been facilitated by the identification of a number
of prostate tissue/tumor antigens that can be targeted, either
by antibody or T cells, to promote prostate tumor cell injury
or death. These same prostate antigens can also be used for
the construction of vaccines to induce prostate-specific T
cell-mediated immunity. Greater insight into specific mechanisms
that govern antigen-specific T cell activation has brought
with it a number of innovative methods to induce and enhance
T cell-mediated responses against prostate tumors. For instance,
autologous dendritic cells loaded with prostate antigens have
proved useful to induce prostate-specific T cell activation.
Similarly, in vivo manipulations of the T cell costimulatory
pathway receptors can greatly facilitate tumor-specific T
cell activation and potentiate T cell-mediated responses against
a number of malignancies, including prostate cancer. Therefore,
in this review we summarize recent advances pertaining to
immunotherapeutic approaches to treat prostate cancer.
[Back to top]
Chemotherapy for Prostate Cancer
S.W. Dyrstad, P. Shah and K. Rao
Androgen deprivation in patients with metastatic prostate
cancer produces palliation of symptoms, reduction in PSA levels,
and temporary regression of tumor in most patients. Following
a brief period of disease regression that lasts an average
of eighteen to twenty-four months, the disease becomes hormone
refractory and progresses. Second line hormonal manipulation
includes anti-androgen withdrawal, glucocorticoids, estrogens,
aminogluthetimide, and keto-conazole. The response from these
drugs is usually very short. Once these measures have been
exhausted, the clinician is left with limited treatment options
that include radionuclides and cytotoxic chemotherapy. It
is the objective of this article to review the experience
with chemotherapy in prostate cancer and then to discuss the
role of radionuclide agents, emerging agents, and herbal therapies.
[Back to top]
Editorial
Each of the major participants in the human hemostatic system,
such as platelets, coagulation, fibrinolysis and vessel wall,
interact with and influence each other. At the start of development
of thrombus formation, platelets adhere and aggregate at the
site of vascular injury. The formed platelet plug is gradually
consolidated and stabilized by fibrin network (coagulation).
Finally, the sequence in the life cycle of a thrombus is represented
by healing of the damaged vessel wall and degradation of the
thrombus by the fibrinolytic system. This cascade tries to
outline how and to which extent these systems interact with
the initial thrombus formation. Many scientists and physicians
have investigated and are much interested in the processes
and interactions involved. Because blood clotting in a vessel
can result in ischemia and necrosis of perfused tissues, it
is important that hemostatic system is carefully controlled.
Moreover, fibrinolytic system is also concerned with proteolytic
system. This phenomenon is recently worth notice on the activation
of many physiological agonists, such as VEGF, FGF and TGF-β.
In preparing this issue, we have focused on each section of
hemostatic system and sought to provide a useful volume for
researchers in this field.
In the first article, Matsuno [1] widely describes a role
of α2-antiplasmin
(α2-AP)
and also mentions about a new aspect of fibrinolytic inhibitors.
α2-AP
is a specific plasmin inhibitor and its physiological effects
are well-known in the development and the degradation of thrombus
formation. Recently, α2-AP
has shown to significantly affect proteolytic formation in
vivo and plays a role of vascular remodeling and heart failure
via VEGF regulation. Moreover, the phenomena show the possibility
that the other physiological substances are also affected
by plasmin.
Ueshima and Matsuo [2] focus on the fibrinolytic system in
the second article. Fibrinolytic compounds have been used
and now the new agents that activate the fibrinolytic system
have been clinically applied for the thrombolytic therapy.
Recently, some derivatives of t-PA have been developed to
obtain the longer half-life than native t-PA and allowed to
administer as the single-bolus. Further, the new fibrin-specific
PA such as staphylokinase and bat-PA have been developed.
Many attempts have been made to develop the drugs that would
induce the release of t-PA from endothelial cells.
The article of Oury and coworkers [3] analyzes in details,
the ADP receptor on platelets. Adenine nucleotides, ADP and
ATP, are co-released from dense granules during platelet activation,
as well as from endothelial cells and damaged red blood cells
following vascular injury. They focused on recent findings
on the physiology of these platelet ADP and ATP receptors,
their distinct downstream intracellular signaling pathways
as well as on the available agonists, antagonists and inhibitors
that allow their pharmacological discrimination.
The paper of Ishisaki and Matsuno [4] stresses the current
view that TGF-β
family seems to play pivotal roles for the development of
atherosclerosis. Especially, TGF-β
and activin A play protective roles against the development
of atherosclerotic plaques. On the other hand bone morphogenetic
protein seems to play pivotal roles for the calcification
of the atherosclerotic plaques. Moreover, it is debatable
whether gene therapy modulating cellular signal transductions
of TGF-β
family is a useful tool for an inhibition of progression of
atherosclerotic disease.
Finally, Kanno and Matsuno [5] provide data on anti-thrombotic
peptides isolated from heart shock proteins (HSPs). Some low
molecular mass heat shock proteins (HSPs) appear to act as
molecular chaperones. Especially, HSP20 shows significant
effects on the prevention of thrombus formation via inhibition
of thrombin. Moreover, 9 amino-acid sequences isolated from
HSP20 or αB-crystallin
significantly reduced platelet aggregation induced by TRAP,
but not a PAR-4 agonist. These findings strongly suggest that
HSP20 or αB-crystallin
can act intercellularly to regulate platelet functions.
In conclusion, the outstanding articles in this issue provide
a current summary to the approach of regulation of hemostatic
system that involves pathological thrombotic formation. We,
therefore, believe that this issue opens a new aspect for
researchers in this field.
References
[1] Matsuno H. α2-antiplasmin
on cardiovascular diseases. Curr Pharm Design 2006; 12(7):
841-847.
[2] Ueshima S, Matsuo O. Development of new fibrinolytic
agents. Curr Pharm Design 2006; 12(7): 849-857.
[3] Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts MF. The
platelet ATP and ADP receptors. Curr Pharm Design 2006; 12(7):
859-875.
[4] Ishisaki A, Matsuno H. Novel ideas of gene therapy for
atheroscrelosis: Modulation of cellular signal transduction
of TGF-β
family. Curr Pharm Design 2006; 12(7): 877-886.
[5] Kanno Y, Matsuno H. The possibility of novel antiplatelet
peptides: the physiological effects of low molecular weight
HSPs on platelets. Curr Pharm Design 2006; 12(7): 887-892.
Hiroyuki Matsuno Ph.D.
Department of Clinical Pathological Biochemistry
Doshisha Women's College of Liberal Arts
Kyo-tanabe, Kyoto 610-0395
Japan
E-mail: hmatsuno@dwc.doshisha.ac.jp
[Back to top]
α2-Antiplasmin
on Cardiovascular Diseases
H. Matsuno
Circumstantial evidence has been provided of a role of the
plasminogen/plasmin system in a variety of biological phenomena,
including thrombolysis, vascular stenosis, reproduction, embryogenesis,
cell invasion, angiogenesis, brain function and chronic lung
or kidney inflammatory disorders. Inhibition of the system
occurs either at the levels of plasminogen activator, regulated
by specific plasminogen activator inhibitors (PAIs) or at
the levels of plasmin, mainly regulated by α2-antiplasmin
(α2-AP).
α2-AP
is a specific plasmin inhibitor. We investigated the role
of α2-AP
on arterial or venous thrombus formation using mice deficient
α2-AP
and the interactions among lack of α2-AP,
antiplatelet, anticoagulant and thrombolytic compounds were
evaluated using murine thrombus model. These results clearly
indicate that α2-AP
plays a different role in acute arterial thrombosis or venous
thrombosis. Additionally, lack of α2-AP
significantly affected anti-coagulant and thrombolytic action,
but not anti-platelet compounds, on the development of thrombus
formation in vivo. Recent findings reported that
plasmin cleaves vascular endothelial growth factor (VEGF)
in extracellular matrix. Our findings newly indicate that
lack of α2-AP
enhances the secretion of VEGF in acute myocardial infarction
and over secretion of VEGF promotes heart failure by pulmonary
edema. Moreover, regulation of VEGF by α2-AP
significantly affected reendothelialization after vascular
injury. These findings indicate a potential new aspect in
this field and could be a useful report for the development
of novel antithrombotic compounds.
[Back to top]
Development of New Fibrinolytic Agents
S. Ueshima and O. Matsuo
Since the activation of coagulation system and platelets
triggers the thrombosis, the agents possessing anticoagulation
or anti-platelet function have been used for the antithrombotic
procession actions. However, in the physiological condition,
the fibrinolytic system serves as antithrombotic, which removes
the thrombus from the circulation. The fibrinolytic system
plays an important role in the dissolution of fibrin, which
is the main component of thrombus. So that, the balance between
the coagulation and fibrinolytic system regulates the formation
of thrombus. Now, the new agents that activate the fibrinolytic
system have been clinically applied for the thrombolytic therapy.
The main factor in fibrinolytic system is the plasmin, which
is activated from the plasminogen by the plasminogen activator
(PA). The plasminogen activator is mainly used for the thrombolytic
therapy. There are two types of PA. One is the non fibrin-specific
PA such as streptokinase (SK) and two-chain urokinase-type
PA (tcu-PA, urokinase), and another is the fibrin-specific
PA such as tissue-type PA (t-PA) and single-chain urokinase-type
PA (scu-PA). Recently, some derivatives of t-PA have been
developed to obtain the longer half-life than native t-PA
and allowed to administrate as the single-bolus. Further,
the new fibrin-specific PA such as staphylokinase and bat-PA
has been developed. Many attempts have been made to develop
the agents that would induce the release of t-PA from endothelial
cells. In this review, the development of new fibrinolytic
agents is summarized.
[Back to top]
The Platelet ATP and ADP Receptors
C. Oury, E. Toth-Zsamboki, J. Vermylen and M.F. Hoylaerts
Adenine nucleotides, ADP and ATP, are coreleased from dense
granules during platelet activation, as well as from endothelial
cells and damaged red blood cells following vascular injury.
Through autocrine and paracrine mechanisms, these extracellular
signaling molecules interact with the platelet P2 receptors
to amplify ongoing platelet activation. Two receptors for
ADP, the Gq-protein-coupled P2Y1 and
Gi-protein-coupled P2Y12 and one receptor
for ATP, the P2X1 ion channel, have been identified
on platelets. Due to distinct pharmacological properties and
differential regulation, the P2Y and P2X receptors essentially
operate on different scales of time and distance and trigger
selective intracellular signaling cascades. Recent advances
in the understanding of the P2Y receptor physiology have reinforced
the concept of these receptors as useful targets for antithrombotic
therapy. The function of P2X1 in platelet activation
only recently started to be unraveled. This review focuses
on recent findings on the physiology of these platelet ADP
and ATP receptors, their distinct downstream intracellular
signaling pathways as well as on the available agonists, antagonists
and inhibitors that allow their pharmacological discrimination.
[Back to top]
Novel Ideas of Gene Therapy for Atheroscrelosis: Modulation
of Cellular Signal Transduction of TGF-β
Family
A. Ishisaki and H. Matsuno
Atherosclerosis is a disease characterized by accumulation
of lipids and fibrous elements in the innermost layer of the
arterial wall. An asymptomatic atherosclerotic plaque is characterized
by a lipid core, composed of modified lipids, macrophages
and T cells, which were separated from the lumen vessel by
a thick fibrous cap, composed of vascular smooth muscle cell-secreted
solid collagen matrix. Recently, it has been reported that
expressions of TGF-β
family were up regulated in human atherosclerotic plaques.
In addition TGF-β
family seems to plays pivotal roles for the de-velopment of
atherosclerosis: TGF-β
and activin A were suggested to play protective roles against
the development of atherosclerotic plaques. On the other hand
bone morphogenetic protein seems to play pivotal roles for
the calcification of the atherosclerotic plaques. Therefore,
it is debatable whether gene therapy modulating cellular signal
transductions of TGF-β
family is a useful tool for the inhibition of progression
of atherosclerotic disease.
In this review, our discussion is focused on the possibilities
of gene therapies for atherosclerosis either by enhancement
or suppression of cellular signaling of TGF-β
family in target cells, in atherosclerotic plaques.
[Back to top]
The Possibility of Novel Antiplatelet Peptides: The Physiological
Effects of Low Molecular Weight HSPs on Platelets
Y. Kanno and H. Matsuno
Some low molecular mass heat shock proteins (HSPs) appear
to act as molecular chaperones, but their exact physiological
roles have not been fully elucidated. We reported on a physiological
role of HSP20, HSP27 and αB-crystallin
on platelet function in vitro and ex vivo.
HSP20 and αB-crystallin
inhibited platelet aggregation using human platelets dose-dependently
induced by thrombin or botrocetin. On the other hand, HSP27,
the other type of low molecular mass HSP, did not affect platelet
aggregation. When HSP20 or αB-crystallin
was injected intravenously as a bolus in hamsters, the development
of thrombus after endothelial injury was prevented. Moreover,
9 amino-acid sequences isolated from HSP20 or αB-crystallin
significantly reduced platelet aggregation induced by TRAP,
but not a PAR-4 agonist. These findings strongly suggest that
HSP20 or αB-crystallin
can act intercellularly to regulate platelet functions. Our
results may provide the basis for a novel defensive system
to thrombus formation in vivo.
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