Current Medicinal Chemistry - Volume 15, Issue 12, 2008

Several observations in mice and in humans have collectively laid the foundation for examining the potential of γ δ T cells to exert tumor immunotherapy. Human γ δ T cells can be activated in a non-MHC dependent fashion either by low molecular mass phosphoantigens, or by agents that provoke the accumulation of endogenous pyrophosphates such as isopentenylpyrophosphate. Among the latter, aminobisphosphonates are well-established in the clinic, and extensive data are available on the compounds' antiangiogenic, antiosteolytic and pro-apoptotic properties. In this review we discuss on the possibility that the intentional activation of γ δ T cells in vivo by aminobisphosphonates may represent a promising target for the design of novel and highly innovative immunotherapy in patients with different types of cancer.

The Src family consists of eight non-receptor protein tyrosine kinases characterised by a common structure. Based on their amino acid sequence, Src family kinases are grouped into two subfamilies, which are also characterised by different tissue specificity. Src kinases are involved in signal transduction pathways triggered by a wide variety of surface receptors, including receptor tyrosine kinases, integrins, G-protein-coupled receptors and antigen receptors. Several pieces of evidence implicate Src family kinases in cancer development, as a consequence of changes in protein expression and/or kinase activity, and have prompted the design of potent specific inhibitors, the most common of which are adenine mimetics, as tools of relevant clinical interest for the treatment of both solid tumours and leukaemias. In addition, the finding that some Src kinases expressed in haematopoietic cells play pivotal roles in lymphocyte maturation and activation has fostered the development of safe and effective inhibitors selective for specific Src family members, which are currently being tested in clinical trials as immunosuppressants for the treatment of immunological disorders. Here we shall review the recent literature on the involvement of Src family kinases in human neoplasias and immunological disorders and the goals reached in the search for selective pharmacological inhibitors.

The management of renal cell carcinoma (RCC) has undergone rapid and radical evolution over the last few years. An improved understanding of the underlying biology of RCC has led to the approval of several new therapies directed against specific and relevant biological targets, so-called “targeted therapies.” These highly effective treatments are now entering routine use, however many questions still remain as to how best to use these agents and integrate them into the broader therapeutic armamentarium. This review summarizes the major published clinical trials of the new agents, discusses the controversies and research questions that have arisen as a result, and considers some of the issues that remain.

Protein kinase C (PKC) family members are multifunctional kinases that have been implicated in many cell biological and physiological tasks including acid, pepsinogen, and mucous production. Through the use of small-molecule PKC modulators, PKC has been found to be involved in gene expression, the control of cytoskeleton, membrane and secretagogue-dependent signal transduction for secretion of acid. Gastric carcinoma and adenocarcinoma cells often show dysregulated PKC-dependent cell signal transduction compared to normal gastric cells. Moreover, PKC was the first known target of tumor promoting phorbol esters. These findings support PKC as a potential chemotherapy target in gastric cancer. Various approaches have been launched in directly targeting PKC for chemotherapy of gastric cancer. The macrocyclic lactone bryostatin-1 is a promising agent that acts as a modulator of PKC activity, and enhances the effect of chemotherapeutic agents such as paclitaxel. This article provides an overview of the findings to date regarding the physiological role of PKC in the gastric cell system by various pharmacological approaches and examines PKC as a target in gastric (adeno-)carcinoma chemotherapy.

Target of Rapamycin (TOR) signaling, originally discovered as the pathway affected by an antifungal macrolide, exemplifies the potential of medicinal chemistry as a discovery tool. Three decades from its identification, signaling involving the TOR kinase has evolved into a complex network with a crucial role in vertebrate growth control. Specifically, it integrates signals to coordinate cell growth (i.e., enhanced mass and size) and cell cycle progression with sufficiency of nutrients, energy, and growth factors. In this review, we discuss multiple aspects of TOR signaling, including cellular regulators and mediators, human diseases related to TOR dysregulation such as cancer, and signaling nodes in the pathway amenable to targeted drug inhibition. The functions and mechanisms of TOR during embryonic development highlight the dynamic role of TOR signaling and reveal additional functions beyond cell growth control. Embryonic TOR signaling has differential tissue-specific and temporal effects, and is involved in organogenesis, sexual differentiation, and epithelial-to-mesenchymal transition signaling. Molecular mechanisms that may contribute to embryonic-specific TOR functions are also examined here. Finally, this review discusses the complex signaling of mTOR in cancer and the development of mTOR inhibitors for cancer therapy.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders. If more effective therapies than the ones currently available are not developed that either prevent AD or other neurodegenerative or block progression of the diseases in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Besides the neuropathologic hallmarks of the diseases, namely neurofibrillary tangles and AD neuritic plaques, the disease is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in basal forebrain. AD and other forms of dementia could be treated by the use of agents which restore the level of acetylcholine through inhibition of both two major forms of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the inhibition of AChE holds a key role not only to enhance cholinergic transmission in the brain but also to reduce the aggregation of β-amyloid and the formation of the neurotoxic fibrils in AD. Following this view, in recent years, an increased interest has emerged directed to finding drugs able to inhibit both of these events. This review summarizes and highlights recent advances in current knowdlege on natural products as cholinesterase inhibitors and how these compounds have also served as the starting points for semi-synthetic analogs with improved properties.

First described in 2000, nephrogenic systemic fibrosis (NSF)/nephrogenic fibrosing dermopathy (NFD) is a recently defined and sometimes fatal condition that, so far, has occurred only in people with some degree of renal failure, either during the conservative phase of chronic renal disease, the dialysis phase, or the kidney transplantation phase. The association between NSF/NFD and gadolinium-based magnetic resonance (MR) examination is so strong that public health agencies have sent out warnings concerning the use of gadolinium-enhanced MR in patients with renal failure. The prolonged residence of some gadolinium-chelates in the uremic milieu may allow free toxic gadolinium released from its chelate to extravasate into the extravascular space where it may accelerate fibrillogenesis. The medical community must be apprised of the concern surrounding the use of gadolinium contrast agent in patients with even moderate renal failure, considering that the number of at risk persons is 20 times greater than that of patients needing dialysis/ transplantation, remember that the risk is particularly high in patients with liver transplantation in the presence of functional renal impairment, and not to forget that MR examination remains one of the three pillars of molecular medicine.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, α-tocotrienol, γ- tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.