Current Medicinal Chemistry - Volume 15, Issue 17, 2008

Degenerative diseases such as cancer usually involve more than one pathological process. Therefore, attempts to combat such diseases with monotherapeutic approaches may not always do so efficiently. For this reason, the use of combination therapy with modalities that target different disease pathways represents an alternative strategy. Photodynamic therapy (PDT) has already been established as an alternative therapy for the treatment of various types of malignant disorders, including oesophageal, lung and bladder cancer as well as other degenerative diseases. This technique involves the administration of a tumor localizing photosensitizer followed by its activation with light of a specific wavelength. In the presence of tissue oxygen, the photoactive sensitizer triggers a series of photochemical and photobiological processes that may lead to direct cancer cell damage, tumor microvascular occlusion and host immune response. Due to these multiple actions, PDT has increasingly gained recognition as a potential adjuvant for conventional cancer treatments. Several preclinical studies and some clinical trials suggest that the use of PDT in combination with established treatments or with newly-developed modalities may be of benefit as compared to the individual modalities. In this review, we briefly introduce the reader to the main photobiological aspects of PDT, and then discuss the use of PDT in combination with other pharmacological approaches for the treatment of cancer.

Pancreatic cancer is one of the deadliest malignancies, costing the lives of more than 30,000 patients every year. It often presents in advanced stages not amenable to surgery. Gemcitabine is currently considered to be the standard of care for the treatment of advanced pancreatic cancer. Combination of gemcitabine with certain other cytotoxic drugs, including cisplatin, oxaliplatin, capecitabine, and 5-fluorouracil have been undertaken, but all have failed to provide substantial increases in survival benefit. However, neoadjuvant algorithms and targeted therapies, including combinations of gemcitabine with erlotinib suggest more promising results. New targeted therapies in combination with gemcitabine are currently in Phase II and III trials, possibly implicating a primary position for them in future treatment. In this paper we present an overview of the current treatment options for the different presenting stages of pancreatic cancer, including adjuvant, neoadjuvant, and targeted therapies, and attempt to provide a comprehensive analysis of the disparate research indicated on this front.

The TNF family member Fas ligand (FasL) induces apoptosis in Fas-expressing cells and serves as a key death factor in the immune system. It is involved in the termination of immune responses by activation-induced cell death, the selection of thymocytes and T and NK cell-mediated cytotoxicity. FasL also participates in the establishment of immune privilege and contributes to tumor cell survival. Besides its death-inducing capacity, FasL has been implicated in retrograde signal transduction into FasL expressing cells by socalled “reverse signalling”. In this context, FasL may also act as an accessory/costimulatory molecule. Dysregulation within the Fas/FasL-system manifests in a severe impairment of the functional integrity and maintenance of immune homeostasis. As its receptor Fas is abundantly expressed in several tissues, the expression of FasL has to be tightly regulated to prevent unwanted damage. At the post-transcriptional level, this is achieved by several independent mechanisms, for example the safe intracellular storage, an activationdependent mobilization, the association with lipid rafts and the shedding by metalloproteases. Of interest, the intracellular portion of FasL contains a unique proline-rich domain, which plays a major role in the control of FasL transport and expression due to interactions with proteins containing SH3 or WW interaction domains. The detailed analysis of FasL-interacting proteins and their functional characterization provided novel insights into the complex processes regulating FasL expression and signal transduction. This knowledge should allow to improve Fas/FasL-based therapeutical approaches that are currently under development.

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.

In the hit to lead process, a drug candidate is selected from a set of potential leads by screening its binding with potential targets. This review focuses on the lead identification assays that employ a bio-chemical or bio-physical test to detect molecular recognition events between proteins and small molecules in a parallel format.These tests require either the lead or the target immobilization followed by incubation with the set of potential interaction partners and detection of a signal related to the target-ligand binding. In the first part of the review the different detection strategies amenable for drug screening are discussed. In the second part, a review of immobilization approaches for leads or targets, allowing the parallel screening of arrays of molecules, is presented.

Recent researches have discovered that MDM2 (murine double minute 2, or HDM2 for the human congener) protein is the main negative regulator of p53, which is an attractive therapeutic target in oncology because its tumor-suppressor activity which can be stimulated to eradicate tumor cells. Inhibiting the p53-MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. A number of drug screening approaches and technologies have been used to identity novel inhibitors of the p53-MDM2 interaction. This review will detail the development history of MDM2 protein and the p53-MDM2 interaction, the major classes of novel small-molecular p53-MDM2 binding inhibitors, key medicinal action with the protein-protein interaction and in vitro or in vivo biological activtiies.

The heart is extensively innervated, and its performance is tightly regulated by the autonomic nervous system. To maintain cardiac function, innervation density is stringently controlled, being high in the subepicardium and the central conduction system. In diseased hearts, cardiac innervation density varies, which in turn leads to sudden cardiac death. After myocardial infarction, sympathetic denervation is followed by reinnervation within the heart, leading to unbalanced neural activation and lethal arrhythmia. Diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, which is a major cause of sudden cardiac death in diabetes mellitus (DM). Despite its clinical importance, the molecular mechanism underlying innervation density remains poorly understood. We found that cardiac sympathetic innervation is determined by the balance between neural chemoattraction and chemorepulsion, both of which occur in the heart. Nerve growth factor (NGF), which is a potent chemoattractant, is synthesized abundantly by cardiomyocytes and is induced by endothelin-1 upregulation in the heart. In contrast, Sema3a, which is a neural chemorepellent, is expressed strongly in the trabecular layer in early stage embryos and at a lower level after birth, leading to epicardial-to-endocardial transmural sympathetic innervation patterning. We also found that cardiac NGF downregulation is a cause of diabetic neuropathy, and that NGF supplementation rescues silent myocardial ischemia in DM. Both Sema3a-deficient and Sema3a-overexpressing mice showed sudden death or lethal arrhythmias due to disruption of innervation patterning. The present review focuses on the regulatory mechanisms involved in neural development in the heart and their critical roles in cardiac performance.

The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT1A receptors has been implicated in the “time lag” observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, DAT, NET, α2-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.