Current Medicinal Chemistry - Volume 15, Issue 8, 2008

There are several types of primary tumors of the central nervous system (CNS), and almost half of them are gliomas. In particular, glioblastoma multiforme (GBM) is very aggressive and infiltrates into the CNS parenchyma. Despite intense clinical efforts, the prognosis of patients with this type of tumors remains very poor, and has not improved in decades, with a median survival of approximately one year after diagnosis. Current treatments include surgical resection, radiotherapy and chemotherapy. However, our knowledge regarding the genetic basis, as well as the molecular signaling pathways involved in the origin and progression of the tumors has increased significantly in the last few years, thus allowing the generation of new chemotherapeutic agents that are used together with sophisticated surgical and radiation techniques. Nevertheless, new approaches are necessary to develop effective treatments for these tumors. One of these novel strategies is gene therapy which is particularly well suited to treat gliomas. In this review we will discuss current therapeutic approaches, as well as critically analyzing gene therapy methods, the use of diverse viral and non-viral vectors, different genes and strategies to treat gliomas, from experimental models to clinical applications.

The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

Despite the conventional and high-dose chemotherapy with hematopoietic stem cell transplantation, multiple myeloma eventually relapses, resulting in an incurable hematological malignancy. Therefore, novel therapeutic approaches in clinical settings are desired. Recently, thalidomide was introduced for the treatment of myeloma, and many clinical trials have since confirmed its efficacy in patients with relapsed/refractory or newly diagnosed multiple myeloma. Multiple mechanisms have been proposed to explain thalidomide's antimyeloma activity. However, the precise mechanism underlying this activity remains unclear, because thalidomide rapidly undergoes spontaneous, nonenzymatic, hydrolytic cleavage to numerous metabolites in vivo. To elucidate the exact anti-myeloma mechanism of thalidomide in vivo, we have performed structural development studies of thalidomide, and obtained various analogs with specific molecular properties. Among these derivatives, we found that a new thalidomide analog, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole- 1,3-dione (5HPP-33), has the most potent anti-myeloma effect with tubulin polymerization inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cells in a dose-dependent manner with IC50 of 1-10 μM. In contrast, thalidomide itself did not inhibit RPMI8226 cell growth. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 had potent tubulin polymerization inhibiting activity with IC50 of 8.1 μM, comparable to that of rhizoxin, a known tubulin polymerization inhibitor. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Our data suggest that 5HPP-33 is a promising candidate as a therapeutic agent for multiple myeloma. In addition, the results suggest that thalidomide's tubulin polymerization inhibiting activity might be the mechanism underlying the induction of apoptosis in myeloma cells.

Alzheimer's disease (AD) is an age-related disorder that causes brain damage resulting in progressive cognitive impairment and death. Three decades of progress have given us a detailed understanding of the underlying molecular mechanisms. Over the past 10 years, this knowledge has translated into a range of targets for therapy, the most promising of which is amyloid β (Aβ). An imbalance between the production and clearance of Aβ is thought by many to represent the earliest event in the pathogenesis of AD. Aβ is known to be subject to oligomerisation, a process that increases its synaptotoxicity. The oligomers may aggregate further to proto-fibrils and fibrils, eventually forming senile plaques, the neuropathological hallmark of AD. In this article we review the key aspects of Aβ as a biomarker for AD, including its pathogenicity, the diagnostic performance of different Aβ assays in different settings, and the potential usefulness of Aβ as a surrogate marker for treatment efficacy in clinical trials of novel Aβ-targeting drugs.

Opioids have been used as pain control medications for thousands of years. Opioids are highly effective analgesics clinically available for controlling moderate and severe pain. Recent genetic knockout and knockin studies have definitively demonstrated that the analgesic effect is mediated through opioid receptors. In addition to their analgesic effect, opioids also have the potential to develop tolerance and physical dependence. Moreover, opioids can modulate cell proliferation and survival. Attempts to design better opioid drugs to eliminate or diminish these undesirable effects for clinical benefits have achieved limited success. In recent years, investigation of the effects of opioid-mediated cell proliferation and survival has been very active, resulting in many publications. However, the molecular targets of such non-analgesic effects are complex. Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the non-analgesic effects, which may be mediated through both opioid receptor signaling and other non-opioid receptor molecular entity-mediated signaling. This review tries to bring the attention of the medicinal chemistry community to new developments and advances in the research areas of opioid-mediated cell proliferation and survival. Further investigation of the molecular mechanism of these non-analgesic opioid effects may eventually yield useful information such as new drug targets, which may be explored to benefit for clinical treatments such as targeted cancer therapy, cancer pain management, regeneration of neurons, and recovery from drug addiction.

Viral proteins sometimes interfere with human transmembrane receptors to gain access into a cell or they use transmembrane domains to interfere with cellular signal cascades in human cells. Such interference can lead to a deregulation of tightly regulated processes and eventually to different forms of cancer. There is still little knowledge about how proteins act and interact in biological membranes but the membrane environment restricts the fold and composition of membrane proteins when compared to water soluble proteins. These restrictions and a sometimes related functional principle of different viral transmembrane proteins for gaining access to a host cell or to intervene with cellular processes may offer a great opportunity to interfere with those processes in a simplified manner. A close collaboration of various disciplines may result in the development of drugs that specifically target membranes and interfere with viral transmembrane domains or even regulate the function of cellular membrane proteins. In this review we describe the function of interactions between human and viral membrane proteins in a cellular membrane, and perspectives to intervene with those processes are discussed.

Purpose of review: Atherosclerosis is a chronic inflammatory disease of the vessel wall. Although it has become common knowledge that hyaluronic acid (HA), an important component of the extracellular matrix, is strongly involved in atherosclerotic disease development it has only recently become evident that HA, instead of being a static matrix polymer, is an active modulator of proliferation and inflammation of the atherosclerotic plaque. This review discusses the regulatory capacity of HA in atherosclerotic lesions and its effects on plaque stability. Recent Findings: The mechanisms by which HA might alter plaque stability are diverse. It regulates cellular migration and proliferation, lipid accumulation, and intraplaque angiogenesis. Smooth muscle cell migration is enhanced upon accumulation of HA, potentially stabilizing atherosclerotic plaques. On the other hand, HA is an important ligand for CD44, which stimulates inflammatory cell recruitment to lesions, leukocyte migration and cell proliferation in atherosclerotic plaques. Furthermore, HA forms complexes with low density lipoproteins, and uptake of these complexes by macrophages is increased compared to native LDL, indicating a more detrimental effect on atherosclerosis. The dynamic functional role of HA might be based on the functional difference between short and larger size fragments of this polymer, with either an inflammatory or an anti-inflammatory besides a pro-mitogenic and anti-mitogenic effect. Low molecular weight HA has been shown to be pro-angiogenic, whereas high molecular weight HA has an anti-angiogenic effect. The cause of these differential actions might be that HA synthesis is regulated by three different genes: HAS1, 2 and 3 leading to different size HA products. These genes are specifically expressed under certain conditions, e.g. HAS1 and HAS3 are selectively induced in inflammation, suggesting an important role of their products in this process. Summary: Hyaluronic acid is an active regulatory component of atherosclerotic lesions. Further studies are warranted to gain more insight into the mechanisms which decide on the role of HA in atherosclerosis and plaque stability.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Dyslipidemia is one of the main risk factors leading to atherosclerosis. Moreover, there is evidence for a role of oxidation in linking lipids and inflammation to development and progression of atherosclerosis. Current therapeutic approaches with lipid-lowering agents, such as statins, fail to protect more than half of patients from cardiovascular events. Therefore, there is a need for additional and alternative treatment options. There are several novel molecules undergoing preclinical or clinical development for the treatment of dyslipidemia or against distinct pathways which contribute to the development of atherosclerosis. Novel squalene synthase inhibitors with significant cholesterollowering and antiatherosclerotic properties are under development. Targeting the production of apolipoprotein B-100 with an antisense oligonucleotide is another interesting approach for lowering low density lipoprotein(LDL)-cholesterol levels. Raising high density lipoprotein( HDL)-cholesterol levels or improving its antiatherosclerotic properties constitute additional attractive targets for protection against CVD. Such compounds include the cholesteryl ester transfer protein inhibitors, HDL-derived proteins, and mimetic peptides/ lipids. Direct targeting of atherosclerosis remains a challenge. Molecules against oxidation and/or inflammation could be beneficial in reducing atherosclerosis. Other targets involved in distinct pathways of atherosclerosis include the lipoprotein-associated phospholipase A2, 5-lipoxygenase-activating protein, acyl-CoA:cholesterol acyltransferase, chemokine receptors, and protein kinases. In conclusion, there are several promising novel therapeutic approaches for dyslipidemia and atherosclerosis under development which are expected to be of great benefit for patients at risk of CVD.

There is a pressing need for the development of new therapies for emphysema, particularly as no existing treatment has been shown to reduce disease progression. Compounds with a potential activity against the pathological mechanisms postulated to play a role in the development and progression of emphysema should be tested in vivo in animal models of this disease. The choice of the model is of capital importance. While models of elastase-induced emphysema are relatively easy to execute, require low personnel capacity and provide fast results, they also have a limited clinical relevance. On the other hand, models of chronic smoke exposure are timeconsuming, expensive and require high personnel capacity but have a high clinical relevance. Presently, mainly two pharmacological approaches are being considered and investigated in experimental studies. The first approach consists of pharmacological interventions designed to slow down the rate at which alveolar wall is lost in emphysema. In this approach we find anti-inflammatory agents, protease inhibitors and antioxidants. The attempt to reduce lung inflammatory cell infiltration is most appealing since such an effect would also reduce the lung burden of both proteases and oxidants. The second approach is an attempt to reverse the process of alveolar loss by inducing alveolar growth. To our knowledge here only the effects of retinoids and/or retinoid receptor agonists have been investigated. This report presents a selected review of the literature of animal studies using these pharmacological approaches.

Tuberculosis (TB) is the leading cause of mortality due to a single infectious agent. The currently used combination drug regimens produce cure rates that exceed 95%, given good patient adherence during the multiple months treatment period. However the recent surge in HIV infections and the synergy between HIV and TB as well as the emergence of resistance resulted in an unforeseen increase in the number of TB cases, including multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB. Consequently, there is an urgent need to develop novel, fast acting antituberculosis drugs with high potency that can provide treatment options for all forms of TB. It is well known that the current TB drugs exhibit differences in their in vivo activity profile and these differences are largely determined by their pharmacodynamics (PD), i.e. intrinsic antibacterial activity, biopharmaceutical properties such as solubility and permeability, and pharmacokinetic (PK) properties such as drug exposure, tissue distribution, and protein binding. An understanding of the relationships among these properties is considered key for a rational use of antituberculosis therapeutics. The current review provides a comprehensive summary of physicochemical/biopharmaceutical, PK, and PD properties of currently used antituberculosis drugs and novel agents under development. Also, a brief review of PK/PD parameters of current TB drugs is given and properties of a desirable TB drug target and drug molecule are outlined. The information provided herewith may be useful in the optimization of biopharmaceutical and PK/PD characteristics in the development of novel TB therapeutics and in the design of optimal treatment regimens.

Microarray gene expression profiling is a high throughput system recently used in basic and applied research. It provides a large amount of data —at molecular level— that once acquired, must be functionally integrated in order to find common patterns within a defined group of biological samples. In addition to identification of differentially expressed genes and the establishment of gene regulation patterns, microarrays may also allow us to discover new tumor markers that could have a great impact on the improvement of clinical practice and therapeutics for cancer. The classification method used for cancer is currently based on the morphological characteristics of the biological samples. The information obtained with this method is limited, omitting many important tumor characteristics like the proliferation rate, the capacity of invasion and metastases, as well as the possible development of mechanisms of cellular resistance to treatment. Microarrays can be used in combination with conventional diagnostics as a helpful complement. In this review we focus on how this technology has contributed to our knowledge of the molecular pathogenesis of meningiomas and schwannomas, its potential role as a useful tool for tumor classification and its application in clinical practice.