Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 3, Issue 4, 2003

Even though the capacity of B-CLL leukemic cells to proliferate has been underestimated until recently, the accumulation of tumor cells in patients mostly results from a defect in the apoptotic program. Several mechanisms can account for this deficient cell death pathway. These include overexpression of antiapoptotic molecules such as members of the Bcl-2 family, which control the opening of the mitochondrial transition permeability pore, and of the IAP (inhibitors of apoptosis) family, which inhibit the activity of caspases. The latter is also suppressed by nitric oxide (NO) released through an inducible NO synthase present in the leukemic cells. The activity of the receptors with a death domain (Fas, TRAIL) is impaired, thus contributing to the resistance to spontaneous and / or drug-induced apoptosis. Interferons as well as several cytokines and angiogenic factors are also involved in the failure of programmed cell death, either by providing efficient signals for survival (BAFF) or by counteracting the apoptotic process. A better knowledge of the mechanisms of survival and escape from apoptosis of B-CLL cells has led to the proposal of new drugs that selectively interfere at the different steps of these cascades. Their study is complicated by the lack of suitable cell lines and pre-clinical models. Nevertheless, some of these chemotherapeutic agents appear to be promising, provided they are correctly targeted to the leukemic cells.

A variety of new anticoagulants for the prevention and treatment of venous and arterial thromboembolism are under development. Designed to overcome the limitations of heparin and vitamin K antagonists, these new agents are at various stages of clinical testing. This paper reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants, describes new anticoagulants in more advanced stages of clinical testing, and provides perspective on how these agents will impact on practice.

Protein kinase C (PKC) represents a family of phospholipid-dependent serine / threonine kinase. PKC was detected in almost all types of cells and tissues in the body. The activation of PKC is involved in the signal regulation of many physiological and pathological processes. PKC has multiple isoforms (α;, βI, βII, γ, δ, ε, η, θ, ξ, ι and μ). PKC-mediated cellular processes are tissue- and isoform-specific. Investigations on selective or isoform-specific PKC inhibitors have attracted great attention during last two decades. Recent studies demonstrated that LY333531, a PKC-β-specific inhibitor, reduced the development of diabetic vascular complications in animal models and prevented hyperglycemia-induced impairment of endothelialdependent vasodilation in healthy subjects. Results from phase I clinical trial suggested low risk of the inhibitor. Phase III clinical trials on the safety and the preventive effects of the PKC-β-specific inhibitor on diabetic complications are under progress. The efficacy of ISSI-3521, a PKC-α antisense inhibitor, on slowing the growth and metastasis of solid tumors is currently being examined in clinical trials. Partial responses in the prevention of the progress of malignancies were found in early phases of clinical trials for UCN-01 and CGP41251, two partially isoform-specific PKC inhibitors. Recent findings suggest that isoform-specific PKC inhibitors are potentially beneficial to the prevention or treatment of some common diseases, including cancers and diabetic vascular complications. Safety and efficacy studies of the PKC inhibitors will be required through large-scale long-term clinical trials.

The accumulation of leukocytes in atherosclerotic lesions is of fundamental importance in the development of atherosclerosis. Consequently, the adhesive and signaling mechanisms responsible for leukocyte invasion in the arterial wall have been intensively studied as potential targets for therapeutic intervention. During recent years, it has become increasingly clear that leukocyte recruitment in atherosclerosis is mediated by a complex series of cellular and molecular interactions that in many ways resemble those that take place in tissue inflammation. However, certain aspects of leukocyte recruitment in atherosclerosis are specific for this disease and present themselves as interesting drug targets. This review summarizes the current knowledge about the mechanisms that guide the extravasation of leukocytes to inflamed tissues, with special focus on atherosclerotic lesions. Moreover, novel experimental techniques are described, techniques that allow for the study of dynamic events taking place in atherosclerosis and that have provided interesting insights into lesion pathology. The data reviewed contribute to the understanding of atherosclerosis, and may help in the development of treatment strategies for a disease that is a major contributor to morbidity and mortality in the western world today.

Recent developments regarding the underlying genetic and intracardiac ion channel causes of congenital long QT syndrome have shed new light in the area of repolarization disorders and their resultant cardiac arrhythmias. Drug induced or acquired QT prolongation often represents a latent form of congenital long QT syndrome, though the genetic basis of this has not been elucidated in the majority of cases. Understanding this has lead to a new concept of repolarization reserve, a measure of inherent susceptilibility to repolarization-mediated arrhythmias. The majority of pharmacologic agents that cause significant QT prolongation have potassium channel blocking characteristics, predominantly affecting the rapidly activating current IKr. The list of agents known to affect IKr continues to grow, best monitored through several websites that collate reports of drug-induced QT prolongation and arrhythmias. Discontinuation of the offending agent and supportive care are often all that is necessary when clinical arrhythmias arise.