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Contents

Organ- and Cell-Type Specific Delivery of Kinase Inhibitors: A Novel Approach in the Development of Targeted Drugs Pp. 1-12
Kai Temming, Marjan M. Fretz and Robbert J. Kok
[Abstract] [Full Text Article]

Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications Pp. 13-23
J.K. Räty, J.T. Pikkarainen, T. Wirth and S. Ylä-Herttuala
[Abstract] [Full Text Article]

Inhibitors of the Ubiquitin-Proteasome System and the Cell Death Machinery: How Many Pathways are Activated? Pp. 24-37
Claudio Brancolini
[Abstract] [Full Text Article]

Apoptosis-Regulatory Factors as Potential Drug Targets in the Epithelium of Normal and Inflamed Airways Pp. 38-49
P.D. Zalewski and R.E. Ruffin
[Abstract] [Full Text Article]

Pharmacology and Therapeutic Applications of Enediyne Antitumor Antibiotics Pp. 50-60
Rong-Guang Shao
[Abstract] [Full Text Article]

Pharmacologic Intervention in Axonal Excitability: In Vivo Assessment of Nodal Persistent Sodium Currents in Human Neuropathies Pp. 61-67
Satoshi Kuwabara and Sonoko Misawa
[Abstract] [Full Text Article]

Immunomodulatory Properties of Antibiotics Pp. 68-79
S.C. Tauber and R. Nau
[Abstract] [Full Text Article]

Targeting Cancer Cells by an Oxidant-Based Therapy Pp. 80-92
J. Verrax, H. Taper and P. Buc Calderon
[Abstract] [Full Text Article]

Abstracts

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Organ- and Cell-Type Specific Delivery of Kinase Inhibitors: A Novel Approach in the Development of Targeted Drugs
Kai Temming, Marjan M. Fretz and Robbert J. Kok

[Full Text Article]

During the past years, we have explored the cellular delivery of kinase inhibitors. Kinase inhibitors have selectivity for specific kinases but they lack cellular selectivity. This is exemplified by recent reports on cardiotoxicity of kinase inhibitors used in cancer treatment. We postulate that targeted cellular delivery of kinase inhibitors can improve their safety/toxicity profiles, as will be exemplified by recent published studies. Cell specific delivery of therapeutics is a quickly growing area of investigation. This innovative strategy employs carrier molecules that bind to receptors exposed on the surface of cell types involved in disease processes. Binding and receptor mediated internalization of the carrier facilitates local accumulation of the product in target cells. Upon systemic administration, this may create local drug depots in specific organs, while other tissues are avoided, thus favoring enhanced localized drug efficacy and reduced side-effects.

Synthesis of targeted kinase inhibitor-carrier conjugates was achieved using a new approach, in which kinase inhibitors were bound to a platinum(II) atom, the so-called Universal Linkage System (ULS). We review this novel linkage chemistry and demonstrate the applicability of ULS for drug targeting approaches aiming at angiogenic endothelial cells, hepatic stellate cells, and kidney tubular cells. We will review important issues like drug release mechanism, safety of the linker, and pharmacokinetics of the products in animals. Finally, we review the pharmacological efficacy of the cellular targeted drug conjugates in experimental animal models, especially in renal and liver fibrosis models.

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Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications
J.K. Räty, J.T. Pikkarainen, T. Wirth and S. Ylä-Herttuala

[Full Text Article]

As gene therapy has matured from clinical trials to the first commercial products, understanding of the mechanisms of gene delivery has increased tremendously. This has also been reflected in viral vector development, creating a number of new approaches to tackle issues in transduction efficiency, biodistribution and viral safety. This review will highlight the most important issues and advancements in vector development, administration, surface modification, integration to host genome and safety. The gene therapy products currently available or near market approval, based on p53 expression (Gendicine™ and Advexin™), conditionally replicative adenoviruses (Oncorine™) and thymidine kinase + ganciclovir therapy (Cerepro®), are introduced with emphasis on the molecular mechanisms of action.

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Inhibitors of the Ubiquitin-Proteasome System and the Cell Death Machinery: How Many Pathways are Activated?
Claudio Brancolini

[Full Text Article]

Over the past decade, the promising results of UPSIs (UPS inhibitors) in eliciting apoptosis in various cancer cells, and the approval of the first UPSI (Bortezomib/Velcade/PS-341) for the treatment of multiple myeloma have raised interest in assessing the death program activated upon proteasomal blockage.

Several reports indicate that UPSIs stimulate apoptosis in malignant cells by operating at multiple levels, possibly by inducing different types of cellular stress. Normally cellular stress signals converge on the core elements of the apoptotic machinery to trigger the cellular demise. In addition to eliciting multiple stresses, UPSIs can directly operate on the core elements of the apoptotic machinery to control their abundance. Alterations in the relative levels of anti and pro-apoptotic factors can render cancer cells more prone to die in response to other anti-cancer treatments. Aim of the present review is to discuss those core elements of the apoptotic machinery that are under the control of the UPS.

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Apoptosis-Regulatory Factors as Potential Drug Targets in the Epithelium of Normal and Inflamed Airways
P.D. Zalewski and R.E. Ruffin

[Full Text Article]

Airway epithelium (AE) lines the conducting airways of the respiratory system and functions to maintain airway integrity by providing both a physical barrier to inhaled noxious agents and a mechanism for their clearance via the mucociliary escalator. Normal AE cells are relatively refractory to a number of apoptotic stimuli and survival mechanisms are in place to maintain the integrity of the epithelial barrier that is exposed to agents such as reactive oxygen species (ROS) and death receptor ligands secreted by immune cells during inflammation. When damage to AE does occur, there is increased AE apoptosis, such as in the airway damage that occurs in the chronically inflamed airways in diseases like asthma where rates of AE apoptosis can be increased many-fold. The usual treatment for persistent asthma in humans involves a combination of bronchodilator and inhaled corticosteroid; there is however a need to develop strategies to better control other aspects of the disease, including minimizing the ongoing damage to AE and consequent airway remodeling. Targeting of the major apoptosis-regulatory factors in AE may be one such strategy. Here we review what is known about apoptosis and its regulatory factors in normal AE and abnormalities in these factors in the inflamed airways of mice and humans.

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Pharmacology and Therapeutic Applications of Enediyne Antitumor Antibiotics
Rong-Guang Shao

[Full Text Article]

The natural compounds that interfere with cellular DNA such as enediyne antitumor antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the enediyne antitumor agents that are approved for clinical use and undergoing pre-clinical or clinical evaluation are reviewed. Most enediyne compounds have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to other chemotherapeutic drugs. Enediyne derivatives, such as an immunoconjugate com-posed of an enediyne compound and monoclonal antibody, reveal stronger activity and selectivity for human cancer cells. The mechanism underlying the anticancer activity of these enediyne antitumor agents may mainly lie in their generation of DNA double-strand breaks. Increasing evidence shows that the enediyne-induced DNA double-strand breaks can engage the activation of DNA damage response proteins, arresting cell cycle progression and eventually leading to apoptotic cell death. Continued investigation of the mechanisms of action and development of new enediyne derivatives and conjugates may provide more effective therapeutics for cancer treatments.

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Pharmacologic Intervention in Axonal Excitability: In Vivo Assessment of Nodal Persistent Sodium Currents in Human Neuropathies
Satoshi Kuwabara and Sonoko Misawa

[Full Text Article]

Axonal excitability testing can provide new insights into the ionic mechanisms underlying the pathophysiology of hyperexcitability of motor and sensory axons in human neuropathies. Threshold tracking was developed in the 1990's to non-invasively measure a number of axonal excitability indices that depend on sodium and potassium channel function, and this makes it possible to monitor the effects of pharmacologic intervention with ion channel modulators. This paper reviews recent advances in ionic-pathophysiological studies in humans. (1) Neuropathic pain or muscle cramp/fasciculation is partly caused by hyperexcitability of the injured axons. The enhanced excitability can result from altered ion channel function; such as an increase in persistent sodium currents. Persistent sodium currents can be reliably estimated using threshold tracking. In peripheral neuropathy, persistent sodium currents usually increase possibly due to over-expression of sodium channels associated with axonal regeneration, and could be responsible for ectopic firings. Administration of sodium channel blockers such as mexiletine, results in marked alleviation of muscle cramping in parallel with a decrease in nodal persistent sodium currents. (2) In diabetic neuropathy, the activation of the polyol pathway mediated by an enzyme, aldose reductase, leads to reduced Na⁺/K⁺ pump activity, and intra-axonal sodium accumulation; sodium currents are reduced presumably due to decreased trans-axonal sodium gradient. Aldose reductase inhibitiors improve nodal sodium currents, as well as nerve conduction, and this can be objectively assessed by threshold tracking. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms by monitoring the corresponding ionic currents. is of clinical relevance, because once a specific ionic conductance is identified, pharmacologic blocking or modulation could provide a new therapeutic option.

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Immunomodulatory Properties of Antibiotics
S.C. Tauber and R. Nau

[Full Text Article]

There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunological and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammtory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in experimental bacterial sepsis, plague and meningitis. Clinically, macrolides have been well established as an adjunctive treatment to β-lactam antibiotics in pulmonary diseases. For other indications, appropriate clinical trials are necessary before using the immunomodulatory properties of antibiotics in clinical practice.

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Targeting Cancer Cells by an Oxidant-Based Therapy
J. Verrax, H. Taper and P. Buc Calderon

[Full Text Article]

Despite the progress achieved in chemo- and radiotherapy, cancer is still a leading life-threatening pathology. In that sense, there is a need for novel therapeutic strategies based on our current knowledge of cancer biology. Among the phenotypical features of cancer cells, two of them are of particular interest: their nearly universal glycolytic phenotype and their sensitivity towards an oxidative stress, both resulting from the combination of high anabolic needs and hypoxic growth conditions. By using menadione (vitamin K3) and ascorbate (vitamin C), we took advantage of these features to develop an original approach that consists in the exposure of cancer cells to an oxidant insult. When used in combination, these compounds exhibit a synergistic action and are devoid of major toxicity in vivo. Thus, this review is dedicated to the analysis of the molecular pathways by which this promising combination exerts its antitumoural effect.