Emerging drugs for renal cell carcinoma

Renal cell carcinoma (RCC) still represents a therapeutic challenge when patients have advanced or metastatic disease. Treatment using IL-2 and IFN-α continues to be the standard of care in patients who are able to tolerate such regimens. Targeted therapy may become the first-line treatment for patients resistant or intolerant to cytokines as new emerging drugs continue to be investigated. Understanding the genetic abnormalities related to the development of RCC (e.g., VHL gene abnormalities) and identifying molecular targets (e.g., epidermal growth factor, vascular endothelial growth factor and carbonic anhydrase IX) are playing a major role in the emergence of these novel agents for the treatment of this malignancy. Overall, these drugs are better tolerated and more acceptable to use by patients than the traditional cytokine-based regimens. The use of oral drugs to treat various malignancies including RCC seems to be the new paradigm of the future. Further understanding of their mechanisms of action and confirmation of their benefits on the clinical outcome is needed.     

Emerging drugs for renal cell carcinoma

Renal cell carcinoma (RCC) still represents a therapeutic challenge when patients have advanced or metastatic disease. Treatment using IL-2 and IFN-alpha continues to be the standard of care in patients who are able to tolerate such regimens. Targeted therapy may become the first-line treatment for patients resistant or intolerant to cytokines as new emerging drugs continue to be investigated. Understanding the genetic abnormalities related to the development of RCC (e.g., VHL gene abnormalities) and identifying molecular targets (e.g., epidermal growth factor, vascular endothelial growth factor and carbonic anhydrase IX) are playing a major role in the emergence of these novel agents for the treatment of this malignancy. Overall, these drugs are better tolerated and more acceptable to use by patients than the traditional cytokine-based regimens. The use of oral drugs to treat various malignancies including RCC seems to be the new paradigm of the future. Further understanding of their mechanisms of action and confirmation of their benefits on the clinical outcome is needed.     

Results of antimicrobial susceptibilities of strains clinically isolated at 8 institutions in Hiroshima City to major oral antimicrobial drugs, mainly new quinolone drugs. Hiroshima Levofloxacin Susceptibility Surveillance Group

To evaluate the resistance for major oral antimicrobial agents, mainly new quinolones, we carried out a drug susceptibility surveillance of 3,050 strains of 11 microbial species clinically isolated at 8 institutions such as general hospitals and examination centers in Hiroshima city. 10 antimicrobial agents were used: 3 new quinolone drugs, 5 beta-lactam drugs, minocycline and clarithromycin. Among Gram-positive bacteria, methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis showed low susceptibility to the new quinolone drugs, while methicillin susceptible Staphylococcus aureus (MSSA) and Streptococcus pneumoniae were highly sensitive to these drugs. Among Gram-negative bacteria, Pseudomonas aeruginosa showed high resistance for the new quinolone drugs, but enteric bacteria and Haemophilus influenzae did not show marked resistance, maintaining almost good sensitivity to these drugs. To reduce the appearance of resistant bacteria, appropriate antimicrobial agents should be selected. Drug susceptibility surveillance in the community will be also important in the future.     

New insights into chemistry and anti-infective potential of triazole scaffold

Research and development for novel substances possessing anti-infective activity have attracted considerable attention due to the escalating resistance towards conventional antibiotics. Therefore, the discovery and development of effective antimicrobial drugs with novel mechanism of action have become an insistent task for infectious diseases research programs. Triazole scaffold has been consistently rewarded as a promising versatile lead molecule with a pivotal position in modern medicinal chemistry. The literature reveals that this heterocyclic moiety has drawn attention of the chemists, pharmacologists, microbiologists and other researchers owing to its indomitable biological potential as anti-infective agents. The present communication is a cogent attempt to review the chemistry and antimicrobial activities of triazole derivatives reported in recent scientific literature. The biological profiles of these new triazole derivatives represent a fruitful matrix for further development as promising and superior anti-infective medicinal agents.     

Aminoacyl-tRNA synthetases: essential and still promising targets for new anti-infective agents

The emergence of resistance to existing antibiotics demands the development of novel antimicrobial agents directed against novel targets. Historically, bacterial cell wall synthesis, protein, and DNA and RNA synthesis have been major targets of very successful classes of antibiotics such as beta-lactams, glycopeptides, macrolides, aminoglycosides, tetracyclines, rifampicins and quinolones. Recently, efforts have been made to develop novel agents against validated targets in these pathways but also against new, previously unexploited targets. The era of genomics has provided insights into novel targets in microbial pathogens. Among the less exploited--but still promising--targets is the family of 20 aminoacyl-tRNA synthetases (aaRSs), which are essential for protein synthesis. These targets have been validated in nature as aaRS inhibition has been shown as the specific mode of action for many natural antimicrobial agents synthesized by bacteria and fungi. Therefore, aaRSs have the potential to be targeted by novel agents either from synthetic or natural sources to yield specific and selective anti-infectives. Numerous high-throughput screening programs aimed at identifying aaRS inhibitors have been performed over the last 20 years. A large number of promising lead compounds have been identified but only a few agents have moved forward into clinical development. This review provides an update on the present strategies to develop novel aaRS inhibitors as anti-infective drugs.     

Antibiotic resistance: who is winning the war? Introductory remarks

The evolutionary response of bacteria, fungi, viruses, and parasites to the selective pressure exerted by antimicrobial agents is the emergence of populations that resist the action of the antimicrobial. The emergence and dissemination of such resistance in a variety of these pathogens is a growing public health concern. In response, the scientific community developed an action plan to address this public health issue. Antimicrobial, antifungal, and antiviral drug development for the treatment of diseases caused by resistant pathogens is one component of this strategy. In addition, due to the targeting of specific drugs against resistant pathogens, we may more readily accept a given drugs toxicity profile for the added therapeutic benefit. This symposium provides a discussion of the modes of action and mechanisms of resistance to antimicrobial agents, and the use of surveillance systems to help understand the nature and magnitude of resistance. The goal is to help guide antimicrobial drug product development and use. Specific toxicity issues are presented that should be considered in phase 1 development of antimicrobial drug products for use in clinical medicine and veterinary medicine. Finally, the national and global strategies developed by federal agencies in the Public Health Action Plan to Combat Antimicrobial Resistance are outlined.     

New investigational antifungal agents for treating invasive fungal infections

Systemic fungal infections have been recognised as a major cause of morbidity and mortality during the last two decades. There are only a few therapeutic options for these infections. Severe toxicity, such as impairment of renal function, limits the use of amphotericin B. Flucytosine is associated with side effects and drug resistance. Fluconazole and itraconazole are safer, though emergence of resistance and innate resistance in some fungal pathogens is a concern in their use. Therefore, there is a need for developing novel drugs and/or treatment strategies to combat these infections. In recent years, increased efforts by the pharmaceutical industry and academia have led to the discovery of new re-engineered or reconsidered antifungal agents that are more efficacious, safer and have a broad spectrum of activity. Lipid formulations of polyene antifungal agents, amphotericin B and nystatin, have the advantage of improved therapeutic index. Activity against resistant fungi, high bioavailability, safety and longer half-life are the properties that encourage development of the newer triazoles (e.g., voriconazole, ravuconazole and posaconazole). Echinocandin-like lipopeptide antibiotics are among the antifungal agents with a novel mode of action. In addition to these lead investigational compounds, development of newer antifungal agents is underway.     

Challenges in antimicrobial drug discovery and the potential of nucleoside antibiotics

Antimicrobial resistance in hospital and community settings is growing at an alarming rate and has been attributed to such organisms as methicillin-resistant staphylococcus aureus, staphylococci with decreased susceptibility to vancomycin, vancomycin-resistant enterococci, multi-drug resistant pseudomonas spp., klebsiella spp., enterobacter spp, and acinetobacter spp., as well as Streptococcus pneumoniae with decreased susceptibility to penicillin and other antibacterials. To address the need for new therapies to combat resistant organisms, drug companies are refocusing their discovery efforts on developing novel agents with new mechanisms of action. The hope is that rapidly emerging technologies including combinatorial chemistry, high throughput screening, proteomics and microbial genomics will have a positive impact on antimicrobial drug discovery. These technologies should aid in the identification of novel drug targets and compounds with unique mechanisms of action other than those currently provided by the traditional antibiotics. Nucleosides are one class of compounds worthy of further investigation as antibacterials since some derivatives have shown moderate to good activity against specific bacterial strains. For example, 5'-peptidyl nucleoside derivatives can inhibit peptide deformylase, an enzyme essential for bacterial survival that is not vital to human cells. This review also includes a list of miscellaneous nucleosides that have been synthesized as potential antibacterials. More detailed investigations on structure, as it relates to the antimicrobial activity of the various classes of nucleosides, need to be conducted in order to maximize the potential of developing a potent nucleoside for the treatment of bacterial infections. This review begins with an introduction to terms followed by discussions regarding the general background and relevance for developing novel antimicrobial agents. Challenges facing the antimicrobial drug discovery process are discussed along with relevant drug targets. An overview of nucleoside chemistry as it relates to antimicrobial activity is presented, followed by a discussion of the evidence which supports the potential of this class of compounds to yield the novel antimicrobial therapies needed in the new millennium.     

Molecular targets of ovarian carcinomas with acquired resistance to platinum/taxane chemotherapy

Ovarian cancer of epithelial origin remains one of the most lethal malignancies despite response rates of more than 80% in first-line combination chemotherapy with platinum drugs and taxanes following surgery. Poor overall prognosis is mainly due to acquired resistance of the recurring tumor mass to initially used and other chemotherapeutic agents. Therefore, novel therapeutic approaches are based on concepts to prevent (improvement of tumor exposure to drugs) or circumvent drug resistance, e.g. with new drugs structurally related to the currently used cytotoxic agents, other types of cytotoxic substances, or with target-specific novel drugs interfering with signaling and apoptotic pathways. In addition, acquired molecular characteristics of drug resistant ovarian carcinoma cells can be defined by expression profiling at different stages of therapy and might be used as specific targets for tumor-suppressing drugs and prodrugs containing cytotoxic components. Revelation of mechanistic details of drug resistance also provides the basis for the development of therapies with novel or conventional antitumor drugs in combination with specific inhibitors able to re-establish chemosensitivity. In this review, we summarize novel approaches in the treatment of ovarian cancer progressed to drug resistant stages and focus on the discussion of recently reported experimental and early clinical results with potentially useful strategies to overcome or modulate acquired drug resistance.     

Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents.

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.     

Discontinued drugs in 2005: oncology drugs

This perspective is the second in a series of papers discussing drugs dropped from development in 2005, of which 20 were being developed for cancer. Of these 20, 60% were biological agents and included 3 cancer vaccine (e.g., Canvaxin?) and 2 antisense oligonucleotide (e.g., aprinocarsen sodium). Overall, 10 cancer drugs were discontinued in Phase I, 6 in Phase II and 4 at Phase III. This paper surveys drugs discontinued in the oncology arena in 2005 by stage of development and class of compound, suggesting some reasons for their failure.     

Discontinued drugs in 2005: oncology drugs

This perspective is the second in a series of papers discussing drugs dropped from development in 2005, of which 20 were being developed for cancer. Of these 20, 60% were biological agents and included 3 cancer vaccine (e.g., Canvaxin) and 2 antisense oligonucleotide (e.g., aprinocarsen sodium). Overall, 10 cancer drugs were discontinued in Phase I, 6 in Phase II and 4 at Phase III. This paper surveys drugs discontinued in the oncology arena in 2005 by stage of development and class of compound, suggesting some reasons for their failure.     

Treatment strategy to eradicate Helicobacter pylori infection: impact of pharmacogenomics-based acid inhibition regimen and alternative antibiotics

The eradication rates of Helicobacter pylori by the triple therapy consisting of a proton pump inhibitor (PPI) and two antimicrobial agents are mainly influenced by bacterial susceptibility to antimicrobial agents and magnitude of acid inhibition during the treatment with a PPI. Acid inhibition during the treatment is affected by the dosing schemes of acid inhibitory drugs (i.e., PPI), genotypes of drug-metabolizing enzymes (i.e., CYP450 2C19), drug transporters (i.e., multi-drug resistant transporter-1) and inflammatory cytokines (i.e., IL-1 beta). Modification of dosing schedules of a PPI, such as frequent PPI dosing and concomitant dosing with a histamine 2-receptor antagonist, could overcome these genetics-related differences in therapeutic effectiveness. For attaining higher eradication rates, the tailored regimen based on the relevant pharmacogenomics is preferable.     

Copper,aluminum, iron and calcium inhibit human acetylcholinesterase in vitro

Acetylcholinesterase (AChE) is an important part of cholinergic nerves where it participates in termination of neurotransmission. AChE can be inhibited by e.g. some Alzheimer disease drugs, nerve agents, and secondary metabolites. In this work, metal salts aluminum chloride, calcium chloride, cupric chloride, ferric chloride, potassium chloride, magnesium chloride and sodium chloride were tested for their ability to inhibit AChE. Standard Ellman assay based on human recombinant AChE was done and inhibition was measured using Dixon plot. No inhibition was proved for sodium, potassium and magnesium ions. However, aluminum, cupric, ferric and calcium ions were able to inhibit AChE via noncompetitive mechanism of inhibition. Though the inhibition is much weaker when compared to e.g. drugs with noncompetitive mechanism of action, biological relevance of the findings can be anticipated.     

P-glycoprotein mediates resistance to histidine kinase inhibitors

Histidine kinase inhibitors are being developed as a new class of antimicrobial drugs. We recently demonstrated the activity of a class of histidine kinase inhibitors against a mammalian enzyme, elongation factor-2 kinase (eEF-2K), and the effect of these compounds on cancer cell viability (Arora et al., 2003). To further characterize these compounds, we studied their interaction with ATP-binding cassette transporters, which are known to mediate resistance to a variety of chemotherapeutic agents. The 24 compounds studied belong to three structural series of derivatives of 2-methylimidazolium iodide. We focused this work on a representative compound (NH125) because we found it to be most potent against both histidine kinase and eEF-2K among the series. Cell lines that expressed P-glycoprotein (P-gp) were 2- to 5-fold resistant to NH125. NH125 increased accumulation of P-gp substrates such as paclitaxel and doxorubicin but had no effect on the accumulation of non-P-gp substrates. P-gp modulators verapamil and trans-flupenthixol and MDR1-targeted siRNA increased sensitivity of multidrug-resistant cell lines to NH125. The presence of a benzyl group on the N-3 position of the 2-methylimidazolium iodide was important for the interaction with P-gp. C6-NH, an NH125-resistant cell line, markedly overexpressed P-gp compared with the parental cell line. In animal models, we found that NH125 increased by 129% the survival of sensitive P388 cells bearing mice but had no effect on mice harboring the resistant cell line. These observations indicate that certain histidine kinase inhibitors are substrates for P-gp and hence an important consideration in development of these agents as potential antimicrobial and anticancer agents.     

Antibody‐Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies

The antibody‐directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non‐toxic prodrugs in cancerous tissue by targeted antibody–enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC‐1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., β‐d ‐galactosidase). Furthermore, the drugs show very high cytotoxicities with IC₅₀ values of as low as 4.5 pm . In this report, we summarize our recent results on the development and biological evaluation of these novel third‐generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.     

Crystallizing new approaches for antimicrobial drug discovery

Over the past decade, the sequences of microbial genomes have accumulated, changing the strategies for the discovery of novel anti-infective agents. Targets have become plentiful, yet new antimicrobial agents have been slow to emerge from this effort. In part, this reflects the long discovery and development times needed to bring new drugs to market. In addition, bottlenecks have been revealed in the antimicrobial drug discovery process at the steps of identifying good leads, and optimizing those leads into drug candidates. The fruit of structural genomics may provide opportunities to overcome these bottlenecks and fill the antimicrobial pipeline, by using the tools of structure guided drug discovery (SGDD).     

New lipid-modifying therapies

Lipid abnormalities are central among the risk factors for the development of cardiovascular disease and their correction remains a major target for the medical community. Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (statins) are the most widely prescribed and best tolerated of the currently available lipid-modifying therapies. Newer agents in this class (e.g., rosuvastatin) have proven to be more effective at lowering levels of low-density lipoprotein cholesterol. New formulations of drugs such as nicotinic acid, which improve treatment regimens and reduce unpleasant side effects, may result in improved patient compliance with this therapy. The development of novel drugs such as cholesterol absorption inhibitors (e.g., ezetimibe) and acyl-coenzyme A cholesterol acyltransferase inhibitors (e.g., avasimibe) will provide clinicians with therapeutic options that exploit different pathways to those currently being utilised. By combining these agents with statins, greater improvements in the lipid profile than those seen to date could be produced. In addition, advances in our understanding of the pathophysiology of dyslipidaemia have enabled other novel therapeutic targets to be identified and studies with experimental drugs underscore the potential of these approaches.     

Salicylanilide ester prodrugs as potential antimicrobial agents--a review

Salicylanilides have been a subject of interest in medicinal chemistry as a group with a wide range of biological activities. The antibacterial (including antimycobacterial) and antifungal activities have come to be viewed as very significant. The synthesis of new prodrugs to counter a number of problematic properties of salicylanilides is a current trend. This article brings together the known basic facts about these prodrugs, particularly about the different mechanisms of the antimicrobial action of salicylanilides, including salicylanilide toxicity and undesired effects. The largest part of this group consists of antimicrobial salicylanilide esters with different organic acids, e.g. acetates, carbamates, esters with N-protected amino acids, and mutual antibacterial compounds with known antibacterial agents (β-lactames and linezolid), with the activity and structure-activity relationships of these compounds being of particular interest. This review summarizes the activity of salicylanilides as potential virulence inhibitors attributable to a blockade of the type III secretion pathway. Many salicylanilide ester derivatives have been demonstrated an effective and promising treatment against pathogenic fungi and bacteria (especially against Gram-positive, tuberculous and atypical mycobacterial strains), including strains such as methicillin-resistant Staphylococcus aureus and isoniazid-resistant mycobacteria which are resistant to one or more clinically used drugs.     

Synthetic strategies and medicinal properties of beta-lactams

More than five decades since the Discovery of Penicillin, the chemistry and biological activity of b-lactams continue to attract the wide spread attention of research workers. Owing to high efficacy and extremely safe toxicological profile, they are agents of choice in the current therapeutic index for the bacterial infectious diseases. Tremendous efforts have been made into synthesis and structural modification of the beta-lactam nucleus to increase antimicrobial activity and pharmacokinetic performance. These efforts resulted in the development of ampicillin, amoxicillin and a group of cephalosporins as clinically effective therapeutic agents. However the rapid emergence of bacterial strains resistant to most generally used members of this class of compound stimulated research for novel beta-lactams, stable to beta-lactamase and possess high potency, broad spectrum of activity both in vitro and in vivo. The mode of action of beta-lactams is to inhibit an enzyme transpeptidase , penicillin binding proteins, critical in the production of bacterial cell wall.