Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 26, 2006

Contents


Dendritic Cell-Based Therapy as a Multidisciplinary Approach to Cancer Treatment: Present Limitations and Future Scopes Pp. 3113-3119
Sk. Md. Fazle Akbar, Masanori Abe, Osamu Yoshida, Hidehiro Murakami and Morikazu Onji
[Abstract]


The Pathology Induced by Highly Active Antiretroviral Therapy Against Human Immunodeficiency Virus: an Update Pp. 3121-3132
Paul Hofman and Ann Marie Nelson
[Abstract]


The Chemical Basis of the Antinitrosating Action of Polyphenolic Cancer Chemopreventive Agents Pp. 3133-3144
M. d’Ischia, L. Panzella, P. Manini and A. Napolitano
[Abstract]


Prevention and Repair of Circulatory Shock and Cerebral Ischemia/Injury by Various Agents in Experimental Heatstroke Pp. 3145-3154
Cheng-Kuei Chang, Ching-Ping Chang, Wen-Ta Chiu and Mao Tsun Lin
[Abstract]


Cardioprotection with Sildenafil: Implications for Clinical Practice Pp. 3155-3164
Shahzad G. Raja
[Abstract]


Purine Nucleoside Analogs as Immunosuppressive and Antineoplastic Agents: Mechanism of Action and Clinical Activity Pp. 3165-3184
Tadeusz Robak, Ewa Lech-Maranda, Anna Korycka and Ewa Robak
[Abstract]


Novel Approaches to Pain Relief Using Venom-Derived Peptides Pp. 3191-3201
Ron C. Hogg
[Abstract]


Immune Modulation and Reconstitution of HIV-1-Specific Responses: Novel Approaches and Strategies Pp. 3203-3211
C.T. Burton, C.M. Mela, G. Rosignoli, S.J. Westrop, F.M. Gotch and N. Imami
[Abstract]


Cysteinyl-Leukotriene Receptor Antagonists: Present Situation and Future Opportunities Pp. 3213-3226
V. Capra, M. Ambrosio, G. Riccioni and G.E. Rovati
[Abstract]


PPAR γ Activity in the Vessel Wall: Anti-Atherogenic Properties Pp. 3227-3238
Allison B. Reiss and Michael E. Vagell
[Abstract]




Abstracts


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Dendritic Cell-Based Therapy as a Multidisciplinary Approach to Cancer Treatment: Present Limitations and Future Scopes
Sk. Md. Fazle Akbar, Masanori Abe, Osamu Yoshida, Hidehiro Murakami and Morikazu Onji

Existence of residual cancers and recurrence of cancers are two major limitations of conventional therapies against cancers. A naturally-occurring defense system against tumor may be established in cancer patients by induction of antitumor immunity. Both polyvalent and tumor antigen-defined vaccines have been administered to cancer patients to accomplish this. However, the efficacy of these approaches is not promising. Dendritic cells (DCs) are regulator of the immune system. Antigens loaded on DCs (antigen-pulsed DCs) are able to induce immune responses when this can not be achieved by administration of antigens or vaccines only. Tumor antigen-pulsed DCs are now used for treatment of patients with cancers. But, it is unlikely that the present regimen of DC-based therapy would be an independent anticancer therapeutic approach. However, the therapeutic potentials of tumor antigen-pulsed DCs can be accentuated in cancer patients if this immune therapy is performed as part of multidisciplinary therapeutic approaches. In this review, we will describe about the concept and limitations of the present regimen of tumor antigen-pulsed DC-based therapy in cancer patients. We will further discuss how DC-based therapy can be applied as a multidisciplinary approach to cancer treatment.


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The Pathology Induced by Highly Active Antiretroviral Therapy Against Human Immunodeficiency Virus: an Update
Paul Hofman and Ann Marie Nelson

The use of highly active antiretroviral therapy (HAART) has considerably improved the quality of life and has increased the survival of HIV-infected individuals. Although HAART can successfully suppress viral replication in the long term, it is not without significant toxicity, which can seriously compromise treatment effectiveness. Moreover, the rapid rate of virus mutation and subsequent emergence of drug-resistant HIV variants threaten the longer-term efficacy of HIV treatment. The most common adverse effects caused by HAART include a metabolic syndrome with lipodystrophy, hyperlipidemia and insulin resistance, deterioration in the clinical status due to various exaggerated local and systemic inflammatory reactions during the immunerestoration disease, and various hepatic, peripheral and cardiac muscle, kidney, bone, bone marrow, retinal, ear, and skin toxicities. The heterogeneity in the organs affected by the different drugs and the morphological features observed in tissues in HAART-treated patients raise possible explanations including differential distribution or activation of these agents. Antiretroviral drugs from new classes, as well as new drugs from existing classes with favorable resistance and side effect profiles are in various stages of development. However, new tissue disorders will be certainly described in the future in patients treated with these drugs. The different pathophysiology of the main adverse effects and the less common known side effects of antiretroviral therapy against HIV are described here, with special emphasis on the histological features induced by HAART.


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The Chemical Basis of the Antinitrosating Action of Polyphenolic Cancer Chemopreventive Agents
M. d’Ischia, L. Panzella, P. Manini and A. Napolitano

A regular intake of polyphenolic agents widely found in fruits and vegetables is believed to decrease the incidence of certain forms of cancer, due in part to their ability to act as antinitrosating agents capable of lowering the impact of toxic nitrosation processes and carcinogenic nitrosamine formation within the acidic environment of the stomach. As a result, the study of the interactions between reactive nitrogen species and phenolic antioxidants has emerged as an area of great promise for delineating innovative strategies in cancer chemoprevention. The burst of interest in (poly)phenolic cancer chemopreventive agents of dietary origin is exemplified by the exponential growth of scientific literature on green tea catechins, as well as on hydroxycinnamates, hydroxytyrosol, flavonoids and other phenolic compounds of the Mediterranean diet, currently regarded as a cultural model for dietary improvement.

However, as is often the case with rapidly growing fields, most of these advances have not yet been assessed nor properly integrated into a well defined conceptual framework, whereby several aspects of the chemistry underlying their mechanism of action have remained either obscure or have been taken for granted without sufficient experimental support. The objective of this paper is to provide an account of the chemical mechanisms through which polyphenolic compounds of dietary origin may react with nitrite-derived nitrosating species under conditions that model those occurring in the stomach and other acidic biological compartments. The relevance of this chemistry to the actual role of these substances in DNA protection and cancer prevention remains a critical goal for future studies.


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Prevention and Repair of Circulatory Shock and Cerebral Ischemia/Injury by Various Agents in Experimental Heatstroke
Cheng-Kuei Chang, Ching-Ping Chang, Wen-Ta Chiu and Mao Tsun Lin

The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4^°C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.


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Cardioprotection with Sildenafil: Implications for Clinical Practice
Shahzad G. Raja

Myocardial ischemia–reperfusion injury occurs in a wide spectrum of patients, ranging from survivors of out-of-hospital cardiac arrest to acute myocardial infarction victims as well as patients undergoing cardiac surgery, and represents a major public health burden. This injury contributes significantly to morbidity and mortality, despite meticulous adherence to presently known principles of myocardial protection. Despite the considerable progress that has been made in the field of myocardial protection, high-risk subsets of patients continue to exhibit ischemia–reperfusion-related complications, including prolonged contractile dysfunction (stunning), low-output syndrome, perioperative myocardial infarction, and cardiac failure, requiring prolonged intensive care. Sildenafil, a phosphodiesterase 5 inhibitor, currently licensed for the treatment of erectile dysfunction and pulmonary hypertension has shown great promise in animal studies as a possible pharmacologic agent for cardioprotection. This review article discusses the pharmacology of sildenafil and focuses on the available evidence from animal studies on the potential role of sildenafil for treating ischemia–reperfusion injury with its implications for clinical practice.


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Purine Nucleoside Analogs as Immunosuppressive and Antineoplastic Agents: Mechanism of Action and Clinical Activity
Tadeusz Robak, Ewa Lech-Maranda, Anna Korycka and Ewa Robak

The purine nucleoside analogs (PNA) form an important group of cytotoxic drugs active in the treatment of neoplastic and autoimmune diseases. Three of them, fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2’-deoxycoformycin, DCF) have established clinical activity in hematological malignancies and have been approved by FDA. These drugs are also investigated in some autoimmune diosorders. Recently four novel PNA: clofarabine (CAFdA), nelarabine, immucillin H (BCX-1777, forodesine) and 8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials.

All these drugs have chemical structure similar to adenosine or guanosine, however, the mechanism of their action is different. FA, 2-CdA and CAFdA mainly require phosphorylation by deoxynucleoside salvage pathways. The cytotoxic effect exerts the triphosphate metabolites, which are incorporated into DNA, and finally lead to programmed cell death. In contrast, DCF does not need to be phosphorylated and results in an increase of plasma deoxyadenosine (dAdo) levels and intracellular deoxyadenosine triphosphate (dATP). Nelarabine is an arabinosylguanine (ara-G) prodrug, which after conversion to ara-G is phosphorylated to ara-G triphosphate (ara-GTP). Accumulation of ara-GTP finally leads to apoptosis. Forodesine is a purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to guanine (Guo), but instead converts it to deoxyguanosine triphosphate (dGTP), and similarly to other PNA resulting in apoptosis. 8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the drug inhibits RNA synthesis, but not DNA .

These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells.

Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid malignancies. 2-CdA and DCF are drugs of choice in the treatment of hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive multiple sclerosis and other autoimmune disorders.

This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials.


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Novel Approaches to Pain Relief Using Venom-Derived Peptides
Ron C. Hogg

More than one and a half billion people worldwide suffer from moderate to severe chronic pain, the National Institute of Health estimates that pain costs health services approximately US$100 billion annually. Existing drugs for the treatment of pain are often associated with serious side effects and rapid development of tolerance, thus, there is a need for new, more selective, molecules. Ion channels play an important role throughout the pain response, from nociception via transient receptor potential (TRP) channels or ATP-sensitive receptors, propagation of action potentials by voltage-sensitive sodium and potassium channels to control of the release of neurotransmitters from presynaptic terminals of dorsal root ganglion (DRG) neurones in the dorsal horn by voltage-gated calcium channels. Venoms are complex mixtures of bioactive molecules that have evolved for prey capture and defence, many of these molecules have a high selectivity for physiological processes, including modulation of ion channel function, which has not been matched by man made molecules. Thus, venoms represent an extensive source of molecules for the development of therapeutic agents. This report will review the key ion channel targets for pain relief, and venom-derived molecules and their analogues acting at these targets. We will concentrate particularly on peptides isolated from Conus venom as these represent one of the best-characterised toxin families. Our current knowledge of the molecular pharmacology of these toxin molecules will be reviewed and problems associated with using peptides as therapeutics will be discussed, along with strategies to overcome these.


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Immune Modulation and Reconstitution of HIV-1-Specific Responses: Novel Approaches and Strategies
C.T. Burton, C.M. Mela, G. Rosignoli, S.J. Westrop, F.M. Gotch and N. Imami

Efficacious protection for future generations from HIV-1 infection through the development of prophylactic vaccines is the best hope for the millions of individuals living with the threat of HIV-1 infection. Advances in the development of non-curative chemotherapy for those already infected have changed the course of the epidemic for those with access to the drugs. However in the ten years since the advent of highly active anti-retroviral therapy, the expectancy of curative chemotherapy has been quashed, and the constant need for a next generation of drugs is evident. As our understanding of HIV-1 pathogenesis increases, it is becoming apparent that novel approaches and strategies will be required to halt the global progression of HIV-1. Immune-based therapies are being considered in the context of effective antiretroviral therapy. Such immune-based therapy must allow the induction or regeneration of HIV-1-specific T-cell responses with the potential to control viremia and purge viral reservoirs. Studies of therapy substitution, treatment interruption, therapeutic vaccines and/or cytokines and/or hormones have been carried out and are briefly summarised in this review.


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Cysteinyl-Leukotriene Receptor Antagonists: Present Situation and Future Opportunities
V. Capra, M. Ambrosio, G. Riccioni and G.E. Rovati

Cysteinlyl-leukotriene receptor antagonists (LTRAs) were introduced as oral preventative anti-asthma medications in the late 1990s and, very recently, montelukast has been approved also for the relief of symptoms of perennial and seasonal allergic rhinitis. Although clinical trials and clinical practice showed LTRAs to be effective in the treatment of asthma patients with a wide range of disease severity, their exact role in the therapy of asthma is not well defined and possibly under-appreciated. As for other anti-asthma drugs, clinical trials with LTRAs uncovered a range of patient responses, so that an understanding of the variability mechanisms (e.g. acquired or genetic factors, etc.) is needed to maximize the probability of a beneficial response. Since the molecular cloning of CysLT receptors (CysLTRs) has been achieved, new roles for cysteinyl-LTs in pathophysiological conditions have been suggested or established from the observed distribution in cells and tissues other than the lung. Cysteinyl-LTs and CysLTRs have been implicated in the pathophysiology of other inflammatory conditions including cancer, atopic dermatitis, idiopathic chronic urticaria, and cardiovascular diseases. As a result, LTRAs might be worth assessing for a therapeutic role in some of these pathologies. This review summarizes and attempts to integrate recent data on the therapeutic efficacy, effectiveness and safety of LTRAs in asthma and allergic rhinitis, and speculates on other therapeutic opportunities.


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PPAR γ Activity in the Vessel Wall: Anti-Atherogenic Properties
Allison B. Reiss and Michael E. Vagell

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor that controls the expression of specific target genes involved in adipogenesis, inflammatory responses, and lipid metabolism. Atherosclerotic plaque progression is influenced by intraplaque inflammation and extracellular matrix deposition. Anti-inflammatory, anti-proliferative and anti-protease activity of PPARγ may modulate the atherosclerotic process. PPARγ is expressed in atherosclerotic lesions of human coronary arteries and has direct anti-inflammatory effects in the vascular wall. Thiazolidinediones (TZD) are ligands for PPARγ used therapeutically to enhance insulin-mediated glucose uptake in persons with type 2 diabetes. These agents may also exert anti-atherogenic effects on cells of the vessel wall including macrophages, vascular endothelium and vascular smooth muscle. This review discusses the impact of PPARγ and its activators in the numerous processes involved in the formation of atherosclerotic lesions. We provide an overview of in vitro and in vivo data in cell lines, animal models, and humans demonstrating the ways in which PPARγ activation alters the biology of the arterial wall.