Drug Design Reviews - Online (Discontinued) - Volume 2, Issue 5, 2005

At present, there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents target unconventional aspects of cancer development, interact with other drugs in an unpredictable manner and are predicted to show clinical benefit in only small subpopulations of patients. How can clinical trials be re-designed to accommodate the new features of targeted anticancer drugs and/or approaches? Herein we will review these obstacles: i) limitations in our knowledge of molecular and systems biology of cancer, ii) application of new agents in inappropriate clinical settings, in unselected patients, and without a clear understanding of the role of the putative target in mediating the antitumour effect. Collection of tissues from models mimicking human cancer at time points that correspond with maximal clinical effect will provide the best opportunity to gain insight into the reasons why agents work or, more commonly, don't work before going into a clinical trial.

Lectins represent a class of proteins that recognize and interact with the carbohydrate moieties on biological polymers. Analyzed here are the lectins that interact with the fucose, the terminal carbohydrate residue of secretory glycoconjugates and plasma membrane glycopolymers of eukaryotic cells. The ability to selectively bind the unique fucose containing determinants, referred to as fine carbohydrate specificity, makes these proteins valuable in experimental and clinical cancer research. This review analyzes the state-of-the-art and recent advances in chemistry, isolation and biomedical applications of fucose specific lectins, the proteins that bind the fucose residues of carbohydrate antigens. Emphasizing the role of fucose containing determinants in cancer progression, the authors focus on fucose specific lectins as the tools for laboratory diagnosis of major human malignancies including leukemia and carcinomas of the colon, stomach and breast. Studies of this class of proteins may be highly productive for both understanding the mechanisms of the disease and for rational design of lectin-based diagnostic and therapeutic reagents.

Most current therapeutic approaches focus on targeting a protein or its function after it has been translated. A therapeutic approach that is gaining interest is altering the mRNA that encodes for a disease associated protein and preventing the protein from being produced. There are two major therapeutic methods to alter mRNA levels, antisense and RNA interference (RNAi). Currently, antisense is the more developed technology and has been extensively used in vivo. As this review will mostly focus on in vivo studies, animal models or humans, it will concentrate on antisense. The lung is an attractive target for this technology as the drug can be introduced to the organ with limited systemic involvement. Inflammatory diseases of the lung, such as allergy or asthma, are potential areas in which antisense technology could be beneficial. There are many mRNA targets being investigated for treatment in inflammatory lung disease that include signaling molecules as well as receptors. Also, antisense is being investigated for treatment of lung cancers. In lung cancer, some oncogenic genes may be unique to the tumor and can be specifically targeted without affecting other cellular processes. Thus, antisense and RNAi potentially provide an alternative to current therapy for treatment of pulmonary disorders.

Nucleosides are currently used in the treatment of many infections caused by viruses and against various cancers. The principal historic limitations of the development of nucleoside drugs that either directly inhibit DNA or RNA polymerases or that inhibit RNA and DNA replication by virtue of their ability to act as alternative substrates for these polymerases, have been the requirements for cellular penetration of the uncharged nucleosides and their subsequent biological conversion to the pharmacologically active nucleoside triphosphate (NTP) species. Unfortunately, intracellular phosphorylation of nucleosides frequently results in toxic by-products, limiting the drug dose that can be administered. In the past few decades, intensive research has provided insights into the nature of chemical and biological requirements associated with the in vitro selective delivery of nucleotides into cells. As such, cleavable protecting groups represent a very powerful tool to increase not only drug delivery but also bioavailability. This review presents an update of prodrug strategies in which the most prominent masking groups currently in use for the treatment of cancer and viral diseases, their stability, toxicities and biological activities are discussed. In particular, the following prodrugs: S-acyl-2-thioethyl (SATE), pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), amino acid esters, and polyethylene glycol drug conjugates will be addressed.

Ionic channels are membrane proteins that can be blocked by many different types of drugs such as local anesthetics, antiarrhythmics, etc. Therefore, they are considered drug targets, whose topology, at the ion channel level, has been analyzed by studying the interactions of specific ion channel blockers and site-directed mutant ion channels. Stereoselective interactions are especially interesting because they can reveal three-dimensional relationships between drugs and channels with otherwise identical biophysical and physicochemical properties. Furthermore, stereoselectivity suggests direct and specific receptor-mediated action, and identification of such stereospecific interactions may have important clinical consequences. However, ≈25% of drugs used in clinical practice are racemic mixtures, the individual enantiomers of which frequently differ in both their pharmacodynamic and pharmacokinetic profile. Furthermore, these different effects induced by one of the enantiomers of a racemic drug may contribute to the undesired effects that can be similar or different to the pharmacological effect of the racemic drug. In other cases, the enantiomers on the molecular target are opposite. In this review, we focus on the stereoselective effects of bupivacaine on different Kv channels. Bupivacaine stereoselectively blocks Kv1.5 and Kv11.1 channels, whereas non-stereoselectively it blocks Kv2.1 and Kv4.3 channels.

Transcription factors belonging to the NF-kappaB superfamily are involved in several human pathologies, as well as in biological processes facilitating the onset of diseases. Among well established functions of NF-kappa B factors is the promotion of osteoclast differentiation in osteopenic diseases, the enhancement of inflammatory processes in cystic fibrosis, the involvement in asthma and pulmonary diseases associated to dust or smoke. In consideration of these roles of NF-kappaB, targeting of these transcription factors could be of great interest. A very promising approach to alter NFkappaB regulated gene expression is the transcription factor decoy (TFD) strategy. The TFD approach employs double stranded oligodeoxyribonucleic acids mimicking the NF-kappaB binding sites or bioactive analogues; therefore, treatment of cells with these decoy molecules causes a binding of NF-kappaB factors to them and not to the target promoter sequences, leading to a strong inhibition of NF-kappaB dependent biological functions. Decoy molecules targeting NFkappaB factors were found in vitro inducers of apoptosis, and strong inhibitors of cell cycle progression, and TNF-alpha induced gene expression in several experimental cell systems. In vivo, decoy molecules targeting NF-kappaB factors were employed for prolonged survival of renal allografts, regression of atopic dermatitis, and cardiac protective effects. Therefore, the design and development of novel molecules able to target NF-kappaB, including modified oligonucleotides, LNA (locked nucleic acids) and peptide nucleic acids (PNA) based transcription factors decoys are of great interest. In this respect, TFD activity of double stranded PNA-DNA-PNA chimeras has been demonstrated to be useful to inhibit NF-kappaB dependent functions.

Modulating agents in combination with major chemotherapeutics have been proposed for restoring drug effectiveness in cellular or parasite resistance. Verapamil was the first in vitro modulating agent reported for resistant malaria followed by psychoactive drugs, natural products and other diverse structural compounds. However, conflicting results for in vitro and in vivo assays and in clinical tests have been reported following the use of modulating agents in combination with antimalarial drugs, mainly, chloroquine. We, herein, demonstrated the failure of modulating agents to restore the in vitro sensibility of Brazilian chloroquine-resistant P. falciparum isolates. In contrast, a significant intrinsic antiplasmodial effect, which was not dependent on the chloroquine combination, was observed. Nevertheless, it is currently recognized that the effectiveness or failure of modulating agents depends on genotypic characteristics, the observed intrinsic activity may be hypothesized based on the common biological or antiplasmodial effect. This may occur due to the structural similarities of chloroquine and the modulating agents. Similar features have also been observed in the new lead modulating agents. In this paper, an overview of the evaluation, use and perspectives of modulating agents against drug and multidrug-resistant malaria is presented.