Current Medicinal Chemistry - Volume 14, Issue 6, 2007

Mathematical models are finding an increasing use in bio-medical scientific investigations as effective means of putting the interpretation of biological phenomena on a more quantitative basis. Besides the well established mathematical paradigm based on differential equations, another approach that takes full advantage of the steadily increasing computing power, is gaining increasing consensus: micro-simulation. Micro-simulation is based on the idea of mimicking the behavior of the system under investigation through the specification of the rules of interaction among its individual constituents. This rule-driven (sometimes called equation-free) approach allows a smoother upgrade of models sophistication and reduces the gap between the abstract level of description typical of mathematical models and the complexity of the biological world. In this article we aim at illustrating, through specific examples, some of the potential advantages that micro-simulation has to offer in order to gain a better grasp and understanding of complex phenomena in biology and medicine.

Aminopeptidase N (APN)/CD13 is a type II metalloprotease that belongs to the M1 family of the MA clan, which consists of 967 amino acids with a short N-terminal cytoplasmic domain, a single transmembrane part, and a large cellular ectodomain containing the active site. APN has a molecular weight of 110,000. The APN exists in two forms namely the membrane aminopeptidase N and the soluble aminopeptidase N. Moreover, it exhibits the presence of various isozymes with different functions. APN is a ubiquitous enzyme present in a wide variety of human organs, tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). It is a multifunctional enzyme, related with tumorigenesis, immune system, pain etc. Furthermore, it also serves as a receptor for coronaviruses and other human viruses. Besides the manifestation of various other functions, APN is also involved in the trimming of antigen and the process of antigen presentation. These functions facilitate the modulation of bioactive peptide responses (pain management, vasopressin release) and influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis) thereby providing treatment options for many kinds of diseases. This review will introduce the structure and main functions of APN briefly.

Regulatory T cells (Treg) encompass a heterogeneous family of T cells implicated in maintenance of tolerance to self antigens. Treg cells might be qualitatively and/or quantitatively deficient in human autoimmune diseases, including multiple sclerosis, graft versus host disease, systemic lupus erythematosus, type I diabetes, and rheumatoid arthritis. In animal models of autoimmunity, infusion of ex vivo-expanded Treg cells and/or in vivo enhancement of Treg cell suppressor function by pharmacological agents and cytokines attenuate disease manifestations and restore tolerance. However, Treg cells represent a double-edged sword, as Treg cells with specificity for tumour-associated antigens contribute to cancer pathogenesis and progression. In vivo depletion of Treg cells by monoclonal antibodies and/or selected drugs is an encouraging therapeutic strategy which improves tumour eradication in animal models of cancer. In addition, elimination and/or functional inactivation of Treg cells might boost anti-tumour immunity in tumour-bearing hosts receiving anti-cancer vaccination. The present review discusses Treg cell manipulation as a novel therapeutic strategy in cancer and autoimmunity, conditions characterised by a common regulatory basis.

Interferon (IFN) was the first cytokine produced by recombinant DNA technology used in wide-spread clinical treatment of infectious diseases as well as malignancies. The IFN clinical potential was clearly realized from the outset. However, IFN represents one of the most controversial drugs of our time, as remarkable cycles of promise and disappointment have affected its development and use. Considerable evidence regarding anti-tumor activities of IFNs has been reported. In this paper we focus on molecular bases of the IFN system that may relate to its antitumor activities. Many of the numerous genes transcriptionally activated by IFNs have been shown to encode proteins that activate immune recognition of tumor cells, directly or indirectly exert tumor suppressor activity and/or control tumor cell cycle and programmed cell death. In addition, a physiological relevant function for endogenous type I IFN in cancer immunoediting process and a new way to IFN clinical use based on gene therapy or vaccine-like approaches have recently been suggested. The identification of selected tissue-specific and/or tumor-specific target pathways as well as of different type I IFN tumor escape and resistance mechanisms may provide novel approaches in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome. Promising IFN treatment has been recently defined by using novel pharmaceutical preparations with a more favourable pharmacokinetic response, also in combination with other bioreagents or other modalities of therapy. Translational research, linking both basic and clinical research, will lead to a new rationale for the use of IFN in cancer therapy.

Imiquimod, the lead compound of the imidazoquinoline family of nucleoside analogues, has shown good efficacy against a variety of tumors of different origin. The mode of action of imiquimod and related compounds, which we have begun to understand in some detail in recent years, is complex and interesting inasmuch as it appears to comprise several presumably mutually enhancing components. Predominant amongst its actions is the induction of pro-inflammatory cytokines through agonistic activity towards Tolllike receptor (TLR)-7 and TLR-8, and consecutively, activation of the central transcription factor NF- κB. This activity stimulates the production of pro-inflammatory cytokines, chemokines and other mediators resulting in activation of antigen- presenting cells and the mounting of a profound Th1-weighted antitumoral cellular immune response. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of NF-κB. The pro-inflammatory activity of imiquimod appears to be augmented by suppression of a negative regulatory feedback mechanism which normally limits inflammatory responses. This is achieved independent of TLR-7 and TLR-8 through interference with adenosine receptor signaling pathways, particularly the A2A subtype, and receptor-independent reduction of adenylyl cyclase activity. Finally, at higher, albeit therapeutically relevant concentrations, imiquimod exerts a pro-apoptotic activitiy against tumor cells. Induction of apoptosis by imiquimod appears to be dependent on Bcl-2 proteins and involves caspase activation. The combination of multiple, presumably synergistic anti-tumoral functions by a single compound represents an interesting principle of pathogenesis-oriented, anti-neoplastic therapy.

Human ABCG2, a member of the ATP-binding cassette transporter superfamily which transports a wide variety of substrates, is highly expressed in placental syncytiotrophoblasts, in the canalicular membranes of liver, in the apical membrane of the small intestine epithelium, and at the luminal surface of the endothelial cells of human brain micro vessels. This strategic tissue localization indicates that ABCG2 plays an important role in absorption, distribution, and elimination of xenobiotics and drugs. High ABCG2 expression has also been detected in many hematological malignancies and solid tumors, indicating that ABCG2 is likely responsible also for the multidrug resistance in cancer chemotherapy. Indeed, ABCG2 can actively transport structurally diverse conjugated- or unconjugated-organic molecules and various anticancer drugs. Many chemo-sensitizing agents have been discovered, which can be developed for increasing drug adsorption and reversing drug resistance in cancer chemotherapy by inhibiting ABCG2 function or expression. This review summarizes current knowledge on ABCG2, its relevance to multidrug resistance and drug disposition, and its evergrowing numbers of substrates and inhibitors.

Oxidative stress, characterized by an imbalance between increased exposure to free radicals and antioxidant defenses, is a prominent feature of many acute and chronic diseases and even the normal aging process. However, definitive evidence for this association has often been lacking due to recognized shortcomings with methods previously available to assess oxidant stress status in vivo in humans. Several in vitro markers of oxidative stress are available, but most are of limited value in vivo because thay lack sensitivity and/or specificity or require invasive methods. Isoprostanes (IsoPs) are prostaglandin (PG)-like compounds that are produced in vivo independently of cyclooxygenase enzymes, primarily by free radical-induced peroxidation of arachidonic acid. F2-IsoPs are a group of 64 compounds isomeric in structure to cyclooxygenase- derived PGF2α. Other products of the IsoP pathway are also formed in vivo by rearrangement of labile PGH2-like IsoP intermediates including E2- and D2-IsoPs, cyclopentenone-A2- and J2-IsoPs, and highly reactive acyclicketoaldehydes (isoketals). Oxidation of docosahexaenoic acid, an abundant unsaturated fatty acid in the central nervous system, results in the formation of IsoP-like compounds, termed neuroprostanes. Measurement of F2-IsoPs is the most reliable approach to assess oxidative stress status in vivo, providing an important tool to explore the role of oxidative stress in the pathogenesis of human disease. Moreover, F2-IsoPs and other products of the IsoP pathway exert potent biological actions both via receptor-dependent and independent mechanisms and therefore may be pathophysiological mediators of disease. Measurement of F2-IsoPs may provide a uniquely valuable approach to understanding of the clinical pharmacology of antioxidants.

During the last few decades, we have witnessed major improvements in the therapy of pulmonary arterial hypertension (PAH). PAH is characterized by abnormal remodeling of the pulmonary artery (PA) and increased PA pressures, resulting in a high premature mortality. Intravenous epoprostenol was the first effective approach toward improving the symptoms and survival of PAH patients. New prostanoids have also exhibited substantial clinical benefits; however, their long-term effects are under investigation. Endothelin-receptor antagonists and sildenafil have increased the lineup of therapeutic options against PAH. Combination therapy using these drugs is promising and is currently undergoing scrutiny in large clinical trials. An extensive analysis of the molecular mechanisms of PAH will produce novel targeted therapies. Most of the promising molecules target the inflammatory and proliferative processes underlying pathological PA remodeling. Interestingly, drugs used for other diseases, such as statins, Rho-kinase inhibitors, imatinib mesylate, may control the pathological vascular remodeling of PAH. Gene and cell therapy using vectors expressing prostacyclin synthase, endothelial nitric oxide synthase, or vascular endothelial growth factor are also promising strategies. However, the efficacy and safety of these approaches should be further tested in clinical trials. Genetic studies revealed some crucial genetic dispositions of familial PAH, although their pathobiological roles have not yet been fully clarified. Collaboration for integrated research will address these issues and generate greater clinical benefits for PAH patients.