Current Drug Targets, Volume 4, No. 6, 2003
Contents
Drug Resistance to Cytotoxic Nucleoside
Analogues Pp. 443-460
L.
Jordheim , C.M. Galmarini and C.
Dumontet
Non-steroidal Anti-inflammatory Drugs and
Cyclooxygenase in Alzheimer’s Disease Pp. 461-468
Jeroen
J.M. Hoozemans , Robert Veerhuis , Annemieke J.M. Rozemuller and Piet Eikelenboom
P-glycoprotein – A Novel Therapeutic Target
for Immunomodulation in Clinical Transplantation and Autoimmunity? Pp. 469-476
Pendse,
S. , Sayegh, M.H. and Frank, M.H.
Inflammatory
Markers and Mediators: Emerging Therapeutic Targets in
Diabetes,
Cardiovascular and Metabolic Disorders
Guest
Editor: Samuel Dagogo-Jack, MD
Novel Cardiovascular Risk Factors and
Macrovascular and Microvascular Complications of Diabetes Pp. 477-486
P.
Theuma and V. A. Fonseca
Insulin Resistance as a Proinflammatory
State: Mechanisms, Mediators, and Therapeutic Interventions Pp.487-492
Rajesh
Garg, Devjit Tripathy and Paresh Dandona
Activated T Lymphocytes in Type 2 Diabetes:
Implications From in Vitro Studies Pp. 493-503
Frankie
B. Stentz and Abbas E. Kitabchi
Aldosteronism in Heart Failure: A
Proinflammatory/Fibrogenic Cardiac Phenotype. Search for Biomarkers and
Potential Drug Targets Pp.
505-516
Karl T. Weber , Ivan C. Gerling , Mohammad F. Kiani , Ramareddy V. Guntaka , Yao Sun , Robert A. Ahokas , Arnold E. Postlethwaite and Kenneth J. Warrington
Abstracts
[Back to top] Drug Resistance to Cytotoxic Nucleoside
Analogues
L.
Jordheim , C.M. Galmarini and C.
Dumontet
Nucleoside analogues are widely used for the treament of hematological malignancies and solid tumors. Their activity is based on the interference with cellular targets involved in the metabolism of physiological nucleosides and DNA synthesis. Unfortunately, various resistance mechanisms decrease the activity of these drugs, reducing their clinical efficacy. Here, we review different resistance mechanisms responsible for decreased in vitro and in vivo nucleoside analogue activity, and some of the strategies proposed to circumvent constitutive or acquired drug resistance.
[Back to top] Non-steroidal Anti-inflammatory Drugs and
Cyclooxygenase in Alzheimer’s Disease
Jeroen
J.M. Hoozemans , Robert Veerhuis , Annemieke J.M. Rozemuller and Piet Eikelenboom
Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer’s disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.
[Back to top] P-glycoprotein – A Novel Therapeutic Target
for Immunomodulation in Clinical Transplantation and Autoimmunity?
Pendse,
S. , Sayegh, M.H. and Frank, M.H.
P-glycoprotein, the human MDR1 gene product and cancer multidrug resistance-associated ATP-binding cassette transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-glycoprotein in the secretion of several T cell- and antigen presenting cellderived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that Pglycoprotein serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional immune responses is now established. Here, we will review the current understanding of Pglycoprotein function in T cell activation and antigen presenting cell function, which are relevant to the fields of clinical transplantation and autoimmunity, and summarize the evidence for in vitro and in vivo immunomodulatory actions of several known P-glycoprotein-inhibiting agents currently in clinical use for other indications. We suggest that it is the Pglycoprotein- inhibitory function of many of these agents that underly their immunoregulatory capacities. Thus, the established immunoregulatory function of P-glycoprotein and the availability of P-glycoprotein-inhibitory drugs raise the possibility that P-glycoprotein may represent a promising novel therapeutic target for immune modulation in acute and chronic allograft rejection, and cell-mediated autoimmune disorders.
[Back to top] Novel Cardiovascular Risk Factors and Macrovascular
and Microvascular Complications of Diabetes
P.
Theuma and V. A. Fonseca
Morbidity and mortality from diabetes mellitus remain high despite managing the traditional risk factors. Recent data imply that the pathophysiology of macrovascular and microvascular complications involve other factors.
The metabolic syndrome precedes the onset of type 2 diabetes by many years. Early treatment of individuals with this syndrome might delay the onset of diabetes and its complications.
Endothelial dysfunction, subclinical inflammation and impaired fibrinolysis may contribute to progression of macrovascular as well as microvascular complications. The roles of infection and hyperhomocysteinemia are less clear but may be significant.
This review discusses the current knowledge on these “non-traditional” risk factors and therapies to improve them.
[Back to top] Insulin Resistance as a Proinflammatory State: Mechanisms, Mediators,
and Therapeutic Interventions
Rajesh
Garg, Devjit Tripathy and Paresh Dandona
Insulin resistance has been recognized as an inflammatory disease based on the scientific evidence collected over the last decade. Inflammatory markers like CRP, PAI-1, IL-6 are present in higher concentrations in insulin resistant people than in normal people. Mechanisms, linking inflammation to insulin resistance are being explored and progress has been made in this direction. TNFa has been shown to be responsible for insulin resistance in obese subjects. Macronutrient intake may also induce inflammation whereas fasting has antiinflammatory effects. Insulin itself has been found to be anti-inflammatory and this action may be useful in many disease states. Thiazolidinediones, such as rosiglitazone that act primarily as insulin sensitisers, have a profound anti-inflammatory and potentially antiatherosclerotic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis, the major complication of insulin resistance.
[Back to top] Activated T Lymphocytes in Type 2 Diabetes: Implications From in Vitro
Studies
Frankie
B. Stentz and Abbas E. Kitabchi
The number of subjects with Type 2 diabetes (DM2) has risen significantly in the last ten years. Obtaining sufficient human tissue to study this disease process as well as many other diseases is generally difficult. T lymphocytes offer a unique opportunity for these studies. Although resting human peripheral T-lymphocytes are devoid of insulin receptors, these receptors emerge upon activation of cells by specific antigens or mitogens. Concomitant with the insulin receptors, two other growth factor receptors (IGF-1 and IL-2) also emerge on the T lymphocyte cell surface along with intracellular signal transduction mechanisms and insulin degrading enzyme (IDE). After binding to its receptor, insulin has been shown to exert its classical effects on carbohydrate metabolism in the stimulated T- cell; thereby, validating the use of activated T-lymphocytes for studying the pathogenesis of metabolic and immune disorders and the mechanism(s) by which insulin exerts its effects. In activated T-lymphocytes, insulin stimulates glucose uptake, glucose oxidation, pyruvate flux and pyruvate dehydrogenase activity, amino acid transport, lipid metabolism and protein synthesis. Through its ability to enhance nutrient uptake and raise the levels of intermediary cellular metabolism, insulin is believed to maintain the allo-activated state of lymphocytes, enhance T-Lymphocyte responsiveness, and support or possibly promote the actions of immuno-derived regulatory growth and differential factors. Since insulin enhances energy requirements and protein synthesis necessary for appropriate T-cell functions, defects in insulin action may lead to inappropriate immunoresponses in various metabolic states such as in diabetes.
Studies from our lab have found insulin binding, processing, and responsiveness in phytohemagglutinin(PHA)-activated T-cells are reflective of the donor's glycemic status and ambient insulin levels in subjects with Type 1 and Type 2 diabetes (DM2) and other insulin resistant states. Our studies show that patients with diabetic ketoacidosis and hyperglycemia have increased proinflammatory cytokines and activated CD4+ and CD8+ T lymphocytes. The diabetic state, where effective insulin concentrations are low and both glucose and free fatty acids are high, provides an environment of oxidative stress and activation of the inflammatory pathways.
The mechanisms underlying insulin action, in general, or in the CD4+ and CD8+ T-lymphocytes, in particular, have not been clearly elucidated. Due to the accessibility of obtaining these cells from patients, activated T-lymphocytes offer the potential of studying diabetes and other disease in human subjects.
[Back to top] Aldosteronism in Heart Failure: A Proinflammatory/Fibrogenic Cardiac
Phenotype. Search for Biomarkers and Potential Drug Targets
Karl T. Weber , Ivan C. Gerling , Mohammad F. Kiani ,
Ramareddy V. Guntaka , Yao Sun , Robert A. Ahokas , Arnold E.
Postlethwaite and Kenneth J.
Warrington
Heart failure is a major health problem of epidemic proportions. Irrespective of its etiologic origins, a dysfunction of this normally efficient muscular pump is associated with systemic consequences, a progressive downhill clinical course and poor prognosis. Ventricular dysfunction is ultimately accompanied by neurohormonal system activation that accounts for: the congestive heart failure syndrome; an induction of oxi/nitrosative stress; adverse vascular remodeling; and activation of the immune system that contributes to a wasting syndrome known as cardiac cachexia. Circulating effector hormones of the renin-angiotensin-aldosterone system are an integral feature of this neurohormonal activation; they have systemic consequences. Insights into the pathophysiology of heart failure will identify improved methods of prevention, including biomarkers to aid in its detection and identification of risk, and to the development of specific drug targets. Herein we address one aspect of the neurohormonal profile of heart failure, namely that related to aldosteronism. Our focus is directed at the link between aldosteronism and its adverse influence on coronary vasculature structure, a proinflammatory/fibrogenic cardiac phenotype, which is based on an immunostimulatory state that includes activated peripheral blood mononuclear cells.