Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 5, Issue 1, 2005

The aim of Current Drug Targets - Cardiovascular & Haematological Disorders is to provide reviews describing new and ground breaking investigative areas of research into therapy for cardiovascular and haematological disorders. Current Drug Targets - Cardiovascular & Haematological Disorders publishes review articles on recent developments in the molecular biology, genomics and biochemistry of drug targets as well as disease specific proteins, receptors, enzymes, genes and diagnosis. The articles from the past year's reviews (2004) have met these aims with outstanding papers on disintegrins, peripheral vascular disease and vascular imaging, among many other excellent reviews on other topics. We would like to thank all of our exceptional authors for their contributions. For 2005 and onwards, I will again extend an open invitation to all authors to write and submit reviews in areas of research into new, therapeutic approaches for the treatment of cardiovascular and haematological disorders. We are looking forward to a truly exceptional year for Current Drug Targets - Cardiovascular & Haematological Disorders.

Current models of oncogenesis describe cancer as a progression of genetic mutations in a tumor cell mass. However, tumors are more than a clonal expansion of malignant cells. Tumors are heterogeneous, with a complex 3D structure, analogous to organs comprised of different tissues. In a tumor mass, the component cell types interact with each other and with their microenvironment by exchanging information through cell-cell interactions and / or through interactions with the extracellular matrix (ECM). These synergetic interactions facilitate tumor progression. Furthermore, tumor invasion and metastatic development are accomplished through the breakdown of ECM. Disruption of ECM promotes abnormal inter- and / or intra- cellular signaling, leading to dysregulation of cell proliferation, growth and cytoskeleton reorganization. The disruption of the ECM in turn promotes the overproduction of growth factors, which induce elevated epithelial cell proliferation and other abnormalities including carcinogenesis. In this review we will demonstrate that hyaluronan (HA), a core component of ECM, contributes to certain types of cancer development. Additional to extracellular HA, intracellular and nuclear forms of HA have been detected. Intracellular HA is involved in cell signaling, whereas nuclear HA could promote chromatin condensation and thus facilitate mitosis. HA molecules are synthesized by hyaluronan synthases (HASs)-HAS1, HAS2 and HAS3 enzymes. Dysregulation of HAS genes results in abnormal production of HA and promotion of abnormal biological processes such as transformation and metastasis. The function of HASs appears to be cell and tissue specific. HAS1 maintains a low, basal level of HA. HAS2 is involved in embryonic and cardiac cushion morphogenesis and subsequent development through cell migration and invasion. HAS2 stimulates cell proliferation and angiogenesis. HAS3 appears to favor the malignant phenotype in many types of malignancies. However, the exact function of HAS isoenzymes and their role in cell signaling remains to be elucidated. A better understanding of HA and HASs may facilitate the design of novel therapeutic strategies to counter presumptive cancer-promoting effects of microenvironmental components.

Drugs, which interfere with the renin-angiotensin-aldosterone cascade such as angiotensin converting enzyme (ACE) inhibitors, have been available to clinicians for more than 20 years. They are now recognized as a very effective approach to treat patients with hypertension, heart failure, diabetic and non-diabetic chronic renal failure or patients with a high cardiovascular risk. The recent development of angiotensin II (Ang II) receptor antagonist has enabled to improve significantly the tolerability profile of this group of drugs while maintaining a high clinical efficacy. Yet, with the availability of Ang II receptor antagonists, new questions have arisen. Is it still possible to gain in efficacy with newer agents? What is the future of drugs such as neutral endopeptidase (NEP) / ACE inhibitors or renin inhibitors? The first objective of this review is to discuss the clinical implications of several large clinical trials that have been published recently with ACE inhibitors and Ang II receptor antagonists such as ALLHAT, LIFE, OPTIMAAL, Val-Heft, SCOPE, and more recently, CHARM, VALIANT and VALUE. With these trials, we can now define more precisely the role of these blockers of the renin-angiotensin system in the management of patients with cardiovascular complications. The second part of this review is devoted to new drugs interfering with the renin-angiotensin system. We discuss the recent results obtained with NEP / ACE inhibitors also named vasopeptidase inhibitors. Several compounds were or are in development but the experience with omapatrilat has blunted the enthusiasms for these compounds. Yet, vasopeptidase inhibitors remain very effective antihypertensive drugs and there is a great therapeutic potential for these agents provided one can define more accurately the risk / benefit ratio and the clinical indications. Finally, we present the recent data obtained with SPP 100, a new renin inhibitor that is actually under clinical development. SPP 100 has a sufficient bioavailability to induce a sustained blockade of the renin-angiotensin system when given orally to normal subjects. Recent studies have shown that SPP 100 lowers blood pressure in hypertensive patients as effectively as an Ang II receptor antagonist.

Recent molecular studies, in particular investigations of subjects with monogenic disorders of lipoprotein metabolism and studies of induced-mutant mice, have increased the understanding of intestinal sterol absorption. Some of these genes encode adenosine triphosphate [ATP] binding cassette (ABC) transporters that transport dietary cholesterol from enterocytes back out to the intestinal lumen, thereby limiting the amount of cholesterol absorbed. ABC transporters also provide an effective barrier against the absorption of plant sterols, which are normally not absorbed in significant quantities by humans. This mechanism was clarified by the discovery that defects in two adjacent genes encoding ABC transporters are the molecular basis of sitosterolemia, a rare autosomal recessive disease in which plant sterols are absorbed due to failure of intestinal barrier to their absorption. Furthermore, recent experiments performed in inducedmutant mice have solidified the importance of these transporters in intestinal sterol absorption. Together with new developments in the biology of bile acids, sterol absorption is providing interesting directions for metabolism research. In addition to elucidating some of the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options to treat hypercholesterolemia and to help patients at risk of vascular disease reach ever-more stringent target levels.

This review focuses on the behavior of metastatic tumor cells and their specific adhesion molecules. Much of this review is based on the results from our researches over many years. Electron microscopic investigations of metastatic processes have demonstrated that desmosomes, tight junctions, or cell fusion-like structures are formed between tumor cells and other cells such as endothelial, mesothelial, hepatic, and nerve cells. These findings suggest that metastatic tumor cells acquire specific cell adhesion or recognition systems. To investigate these adhesion mechanisms, we established floating sublines from rat ascites hepatoma AH7974 in vitro and compared their adhesion molecules with those of their adherent counterparts. The anchorage independence of these tumor cells can be explained by reduced production of extracellular matrix proteins, decreased expression of cell surface integrin(s), or lack of heparan sulfate proteoglycans on the cell surfaces. Although the metastatic potential of these sublines for lung could not be explained by these properties, it may be explained by expression of 56 and 62 kDa laminin-like substances containing Griffonia Bandeirea simplicifolia isolectin B4-binding carbohydrate(s). We examined the relationship between carbohydrate expression and metastasis of human breast, pulmonary, colorectal, gastric, and other cancers by using a panel of lectins and monoclonal antibodies (MAbs). These studies revealed that several lectins and MAbs such as Vicia villosa agglutinin (VVA), Helix pomatia agglutinin, anti-sialyl Lewis x-i MAb, and others were useful not only for predicting metastasis and the prognosis of patients but also for understanding the routes of metastatic spread. VVA-binding carbohydrates, i.e. Nacetyl- D-galactosamine residues, especially those carried by atypical MUC1 protein, in aggressive cancer cells may serve as an important drug target.

Nitric oxide (NO) is a small gaseous molecule with an odd number of electrons and is rather soluble in hydrophobic phases. It was once known for its toxicity in the environment and for its applications in meat curing. After 1980 its importance was discovered in many physiological fields such as vascular regulation, neuronal communication, cytotoxic action by macrophages in bacterial infections etc. On the other side NO is involved in toxic shock, DNA damage and many pathological conditions. In 1992 the journal Science designated it as “molecule of the year” and in the last years there has been an explosion of publications on the subject. The publications are concerned with the spectroscopic characterisation of NO derivatives, with the reactivity of NO with Myoglobin, Cytochrome and Hemoglobin and in particular with the chemical activities and biological applications of nitric oxide donors and nitric oxide scavengers. All such researches have produced until now many patents. The most famous products are Viagra and nitroglycerine (Trinitrin). Particular attention is given to the applications of NO to cardiovascular and hematological disorders. To this aim the authors examine the physiologic activities of NO and the mechanism of its antiplatelet, vasodilatory and antiproliferative action. Studies in animals and humans are also reported. Another section examines the drugs that increase the endogenous production of NO and modulate its activities. The last part is dedicated to the novel antithrombotic agent Nitroaspirin. Methods for NO detection will also be examined.

Azimilide is an investigational Class III antiarrhythmic that has been developed for treating both supraventricular and ventricular tachyarrhythmias. Similar to other Class III antiarrhythmics, azimilide prolongs myocardial repolarization in a dose-dependent manner by increasing the action potential duration, QT interval, and effective refractory period. The most frequent reported side effect is headache, with rare serious adverse events of early reversible neutropenia and Torsades de Pointes. In long-term follow up, the patient withdrawal rate has been low. Azimilide has very predictable pharmacokinetics, is predominantly hepatically metabolized, and has no significant drug interactions with digoxin or warfarin. In animal models, azimilide has been shown to be very effective in suppressing both atrial and ventricular tachyarrhythmias, decreasing the defibrillation energy requirement, and preventing post-myocardial infarction ventricular tachycardia and fibrillation. Clinically, in a series of 4 double-blind, randomized, placebo-controlled trials, the Azimilide Supraventricular Arrhythmia Program which included over 1000 patients and approximately 70% with structural heart disease, azimilide showed a significant prolongation in the time to first recurrence of paroxysmal supraventricular tachycardia or atrial fibrillation / flutter. With respect to ventricular tachyarrhythmias, the AzimiLide post-Infarct surVival Evaluation Trial was a large randomized, multinational, prospective, placebo-controlled study in recent survivors of myocardial infarction at high risk for sudden cardiac death. After 1 year of follow-up, this study showed no statistical difference in all-cause mortality between placebo and azimilide. However, azimilide did statistically reduce the incidence of new atrial fibrillation. Further trials are necessary to evaluate the efficacy of azimilide in patients with symptomatic ventricular arrhythmias.

P2 receptors are a class of plasma membrane receptors ligated by extracellular nucleotides and expressed ubiquitously throughout the body. Two main families are known: P2X and P2Y. P2X are ligand (ATP)-gated channels, while P2Y are G-protein-coupled seven membrane-spanning receptors. The P2X and the P2Y subfamilies comprise seven and eight members, respectively. While ATP is the only known physiological ligand of P2X receptors, P2Y receptors are known to be also activated by ADP, UTP, UDP and UDP-glucose in a subtype-specific manner. Several P2 subtypes are expressed by leukocytes where they have been implicated in a host of different responses ranging from chemotaxis to differentiation, from proliferation to cytotoxicity, from secretion of inflammatory mediators to cell fusion. However, until recently there was no in vivo proof of the participation of P2 receptors in inflammatory or proliferative disorders and, in addition, few pharmacological modulators of P2 function were available. During the last two years animal and human studies have produced preliminary but nevertheless compelling evidence in support of an important function of P2 receptors in inflammation and hematological tumors. Importantly, selective blockers of these receptors have been synthesized, thus paving the way to the possible development of P2-targeted anti-inflammatory and anti-tumoral therapies.