Current Pharmaceutical Design - Volume 12, Issue 7, 2006

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 5a-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.

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.

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 therapy. 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 natural 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.

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.

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 tumorspecific 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.

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 ketoconazole. 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.

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 singlebolus. 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 ........

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.

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.

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.

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 development 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.

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 αBcrystallin 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.