Antitumor photochemotherapy: biochemical bases, therapeutic uses and perspectives]

The photodynamic therapy of tumors (PDT) is a recent and promising technique for the treatment of tumors which can be reached by the light (directly or by endoscopic illumination). Excellent results are now obtained with hematoporphyrin derivatives such as Photofrin II, provided the concerned tumors are small and well delimited. Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. In the present paper, after a brief presentation of the biochemical basis of the light-dependent cytotoxicity of porphyrins, we shall examine the role of lipoproteins, especially LDL, in the transport and the cellular uptake of these compounds. We shall also present recent approaches for the improvement of the PDT efficiency.     

Current perspectives on therapeutic antibodies

Since the first monoclonal antibody, muromonab-CD3, was approved for therapeutic use in 1986, numerous molecules have been targeted using therapeutic antibody technology, resulting in 26 therapeutic antibodies being approved by the US FDA as of November, 2009. Initial concerns regarding antibody drugs focused on immunogenicity, short serum half-life, and weak efficacy. As the types of antibodies progressed from murine to chimeric, humanized, and fully human antibodies, great progress has been made in immunogenicity and in vivo instability issues. For example, humanized antibodies, such as bevacizumab, exhibit less than 0.2% immunogenicity and a 20 day serum half-life, which is comparable to native immunoglobulin. Some recently developed antibodies are exceedingly efficacious and have become first-line therapy for their target diseases. Here, we address and analyze all clinically approved therapeutic antibodies to date by discussing immunogenicity, half-life, and efficacy.     

Concepts and therapeutic perspectives of proteomics

The present paper aims at clarifying some important aspects of proteomics, i.e. the large scale analysis of proteins. To this purpose, the main types of proteomic analyses are presented, i.e. those aiming at determining expression levels and those aiming at unravelling protein-protein interactions networks. Their performances and limitations are outlined, as well as their potential applications in biomedicine, to give an reasoned view of the current state of the art.     

Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer

The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.     

Translational research and therapeutic perspectives in dysferlinopathies

Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.     

Stimulating effects of carnosine on hemopoietic stem cells]

It was shown that intake of carnosine in a dose of 50-100 mg/kg of body weight before X-ray irradiation resulted in an increase of the survival of experimental mice. The protective effect of carnosine was manifested, when it was injected either before or after irradiation, but the effect was more pronounced in the case of shortening time between irradiation and injection. An enhancement of colony forming index of bound cells in spleen was also observed simultaneously with protective action of carnosine. These effects are supposed to be the result of immunomodulating activity of carnosine.     

Macrolides: new therapeutic perspectives in lung diseases

There is strong clinical evidence for the effectiveness of macrolides in the treatment of a number of chronic airway diseases through their immunomodulatory effects. Recently, new information has been released supporting the view that macrolides may also be beneficial in pathologic situations associated with altered repair of the alveolar structure, such as those observed in interstitial lung diseases and fibrosis. It is proposed that macrolides may contribute to lung regeneration through their actions on several components of the remodeling process. The present review provides new insights on the effects of macrolides on the regenerative response of alveolar epithelium to injury. It also discusses novel findings which suggest that macrolides may contribute to alveolar surfactant homeostasis.     

Melatoninergic receptor agonists and antagonists: therapeutic perspectives

The chronobiotic neurohormone melatonin, synthetized in the pineal gland during darkness periods governs the circadian and seasonal biological rhythms. Physiologically, melatonin regulates the sleep/activity alternance, together with the circadian cycle of body temperature and cortisol secretion, and influences various immune, endocrine and metabolic functions. Dysfunction of the endogenous melatonin secretion is associated with mood and behavioral disorders including body weight. Patients with severe depression exhibit desynchronized and reduced melatonin secretion, in parallel with marked sleep disturbances whereas exogenous melatonin administration and antidepressive drugs restore melatonin secretion. A dysregulated melatonin secretion is also observed in obese subjects. Implication of melatonin in these disorders stimulated the search for melatonin analogues with enhanced antidepressive and body weight control effects. The melatoninergic agonist S 20098, or agomelatin, disclosed a potent antidepressive and anxiolytic activity in preclinical studies, which was confirmed in clinical trials in patients with major depression. The antagonist S 20928 was shown to limit seasonal weight gain in an hibernating rodent model. Thus, development of melatoninergic agonists and antagonists appear as an innovative approach in the treatment of depression and obesity, two major public health problems.     

Stem cells: properties and perspectives of therapeutic use

In the present work, we review the properties of some stem cell types, namely embryonic, hematopoietic and mesenchymal stem cells, which present the most significant interest for use in medicine. Stem cells are undifferentiated cells capable of both self-maintenance and differentiation into mature specialized cells. According to their origin, stem cells can be classified as embryonic and somatic ones. The first ones can be indefinitely maintained in culture, and possess the ability to differentiate into all cells of the adult organism. The second ones possess the limited capacity to differentiate and, probably, a limited proliferative potential. For therapeutic use, important but hotly debated is the plasticity of somatic stem cells, i.e. context-dependent differentiation into "non-related" cell types. It is assumed that the differentiation of the majority of stem cell types proceeds according to the principle of stepwise hierarchical maturation through the stage of intermediate rapidly proliferating progenitor cells. The use of stem cells in medicine is mostly at the preclinical stage now. Despite the fact that embryonic stem cells are highly promising as therapeutic agents, a number of circumstances substantially limits their therapeutic use in the near future. At the same time, approaches involving autotransplantation of hematopoietic or mesenchymal stem cells are beginning to be applied successfully in the clinical trials for treatment of limb ischaemia and myocardial infarction. It is clear that despite a large number of problems and unsolved questions, the use of stem cells in medicine promises a dramatic progress in the treatment of many severe diseases.     

Airway remodeling in asthma: mechanisms and therapeutic perspectives

Although asthma is classically defined as reversible airflow obstruction and often remits in younger subjects with milder disease, a proportion of asthmatics experience chronic symptoms, episodic exacerbations and persistent airway obstruction, despite the continuous use of beta 2-agonists, associated with high doses of inhaled/oral corticosteroids. These patients contribute to the majority of asthma costs through hospitalization, emergency visits, absence from work or school and use of medication. Although the mechanisms behind irreversible airflow obstruction in asthma are unclear, a prominent role has been attributed to persistent structural changes of the bronchial wall, defined as airway remodeling. Studies conducted on endobronchial biopsy samples have led to the histopathological characterization of these tissue alterations, which include chronic mucosal inflammation, extensive epithelial damage, collagen deposition, subepithelial fibrosis, increased mucous glands and airway smooth muscle hypertrophy and/or hyperplasia. Several factors, such as polypeptide growth factors and their receptors, matrix metalloproteases, intracellular molecules controlling cell death and survival, adhesion molecules and their ligands, as well a large variety of cytotoxic pro-inflammatory mediators are likely to contribute to the onset and maintenance of these tissue abnormalities. However, to date, the cellular and molecular events driving specifically these phenomena and allowing asthmatics with persistent airflow limitation to be distinguished from patients who normalize their bronchial obstruction upon adequate therapeutic management have not been identified yet. Accordingly, airway remodeling represents a major research challenge, particularly in view of the development of new therapeutic strategies specifically addressed at alleviating persistent bronchial obstruction in these otherwise intractable patients.     

Synthetic and therapeutic perspectives of nitrogen containing heterocycles as anti-convulsants

Epilepsy is one of the commonly prevailing neurological disorders. According to the reports, it is evident that about 80% of the epileptic cases have been observed in developing countries. Although there are many drugs with significant potency available in the market; still there is an issue of selectivity and toxicity. Therefore, continuous attempts have been made by the researchers to develop newer therapeutic agents against epilepsy. Many synthetic strategies have been available in the literature to synthesize various classes of anticonvulsants with promising activity. In the presented review, authors have summarized some newer synthetic routes being used for the synthesis of nitrogen-containing anticonvulsants taking a cue from the reported established anticonvulsant drugs viz. vigabatrin, sodium valproate, oxcarbazepine, felbamate, retigabine, and gabapentin. Various derivatives with the substitution for better anticonvulsant profile have been described in the figures for easy comparative study. The structure–activity relationship (SAR) of compounds with maximum potency has also been discussed. This article may serve as a boost for the researchers to modify the pre-existing synthetic routes as well as to improve potency and yield of the compounds.     

Lysine transport across the small intestine. Stimulating and inhibitory effects of neutral amino acids

Summary The ordinary aliphatic, neutral amino acids and phenylalanine have been examined for cis-inhibition of influx of alanine (J _mc ^ala ) and lysine (J _mc ^lys ) and trans-stimulation ofJ _mc ^lys across the brush border membrane of rat small intestines: and their effects on the unidirectional mucosa-to-serosa flux (J _ms ^lys ) across the short circuited intestine have been studied. The effects of alanine, -amino-n-butyric acid, leucine, and methionine on the steady-state epithelial uptake of lysine [Lys] _c have also been measured. In addition the trans-effects of alanine and leucine have been examined for sodium-dependence, and alanine was tested as trans-stimulator of influx of galactose across the brush border membrane (J _mc ^gal ).All the neutral amino acids were found to be competitive cis-inhibitors ofJ _mc ^lys , and all, except isoleucine, were trans-stimulators ofJ _mc ^lys . The magnitude of the trans-effect was unrelated to the efficiency of the amino acid as cis-inhibitor. As illustrated by alanine, the trans-effects are probably completely sodium-dependent. Alanine was also effective as trans-stimulator ofJ _mc ^gal . With respect to effects on [Lys] _c andJ _ms ^lys the neutral amino acids fall into two groups: One which reduces [Lys] _c and stimulatesJ _ms ^lys , and one which increases [Lys] _c and relatively inhibitsJ _ms ^lys . These effects are not correlated with the affinities of the neutral amino acids for the two carriers involved.It is proposed that the trans-effects onJ _mc ^lys are induced by an electrogenic, sodium-coupled efflux of the neutral amino acid across the brush border membrane, that the stimulation ofJ _ms ^lys is brought about by a selective stimulation (of unknown nature) of efflux of lysine across the basolateral membrane (J _cs ^lys ), assisted by competitive inhibition of lysine efflux across the brush border membrane (J _cm ^lys ), and that the amino acids which do not stimulateJ _cm ^lys increase [Lys] _c by competitively inhibitingJ _cs ^lys andJ _cm ^lys .The inhibitory effect of the neutral amino acids onJ _mc ^lys support the view that the carrier of basic amino acids serves as a second carrier of these amino acids.     

Pharmacological studies of somatostatin and somatostatin-analogues: therapeutic advances and perspectives

This article is aimed at reviewing and analyzing studies that are related to the possible therapeutic use of a potent and ubiquitously-distributed hormone--somato-statin (SS-14), and its analogues. Administration of these substances has provided beneficial effects in treating acromegaly, gastro-intestinal hemorrhagic and hypersecretory disorders, acute pancreatitis, diabetes mellitus, and certain types of cancer. Further studies with SS-14-analogues might provide new therapies for treating certain life-threatening disorders of man.     

Diagnostic perspectives of mobile radiographic computerized tomography]

The authors assess mobile methods of x-ray computer-aided tomography (CAT) and suggest an organization and methodological scheme of its application. Their program of the first and up to now the only one in this country mobile CAT device is based on the new principles of mobile CAT application. It is realized in special hospitals of large regions, where the patients with the optimal indications for CAT are assembled. Over 15,000 examinations were carried out with the use of the suggested CAT program over 4 years, that resulted in detection of 1295 brain tumors, 804 cases with neoplastic involvement of the abdominal cavity and the retroperitoneal space. The authors claim that wide application of mobile CAT devices according to the program they suggest will help decide the problem of unavailability of such examinations, for it will rule out the principal cause of this unavailability--economic problems arising because of high price of this equipment. One mobile device may replace 3 permanent CAT devices, if used according to the program suggested by the authors.     

Stimulating effect of histones on DNA synthesis in the regenerating rat liver]

Effect of exogenous histones, nuclear globulins and acid proteins on DNA synthesis is studied in regenerating liver of rats in which the synthesis of their own proteins and thus DNA replication are inhibited by cycloheximide. In these conditions histones from regenerating rat liver are found to stimulate 3H-thymidine incorporation into DNA of hepatectomyzed rat liver. Nuclear globulins and acid proteins from regenerating liver, and histones from intact liver produced no stimulating effect on DNA sythesis.