Current Pharmacogenomics - Volume 3, Issue 4, 2005

The ability to induce and/or monitor an immune response to a broad repertoire of epitopes universally recognized across continents and genetic backgrounds is considered a critical characteristic of an effective vaccine and diagnostic tool. Opportunities for epitope identification are expanding as the number of entirely sequenced pathogens approaches 500 and access to this data improves. The pace of vaccine design will accelerate as bioinformatics are systematically applied to whole genomes and used in combination with in vitro methods for screening and confirming epitopes. Given access to bioinformatic tools, epitope-driven diagnostic tools and both preventive and therapeutic vaccines (for infectious diseases of worldwide impact such as tuberculosis and HIV) are now within our reach. This review describes the structural basis of the bioinformatic tools for epitope prediction methods as well as the recent use of these approaches at genomic level in the development of diagnostic tools and vaccine design as example of structural bioinformatic system applied to pharmacogenomics.

Aminoglycoside antibiotics have long been used as antibacterial agents due to their ability to inhibit bacterial translation. However, aminoglycosides also stimulate translation errors in mammalian cells. Aminoglycosides bind to a pocket formed in a domain of the ribosomal RNA (rRNA) of the small ribosomal subunit that constitutes the decoding site in both prokaryotes and eukaryotes. Normally, accurate base pairing takes place between each successive codon and its cognate aminoacyl-tRNA within this region of the ribosome. When aminoglycosides bind to the decoding site, a conformational change decreases discrimination between cognate and near-cognate tRNAs, leading to errors in the decoding process. The ability of aminoglycosides to bind to the decoding site and induce translational misreading in eukaryotic cells is less efficient than in prokaryotic cells due to subtle differences in the sequence of the decoding site rRNA. The observation that aminoglycosides induce low levels of misreading in eukaryotic cells has inspired many investigations to determine whether aminoglycosides can suppress nonsense mutations that cause human diseases. Disease models in which aminoglycosides have been shown to efficiently suppress nonsense mutations include cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome, infantile neuronal lipfuscinosis, cystinosis, x-linked nephrogenic insipidus, spinal muscular atrophy, and cancer. However, if aminoglycosides are to be used clinically for suppression therapy, their efficacy must be improved and their toxicity reduced. The co-administration of other compounds that reduce aminoglycoside toxicity or the development of new compounds that suppress stop mutations may allow the realization of suppression therapy as a clinical treatment to suppress disease-causing stop mutations.

Hypertension affects 60 million Americans and is the most common disorder for which medications are prescribed in the USA. Hypertension associates with serious complications including stroke, heart failure, ischemic heart disease, and renal failure. Racial background associates with the prevalence and complications of hypertension with African Americans more frequently and severely affected. Hypertensive African Americans demonstrate different responses to antihypertensive medications compared to other ethnic groups and specific candidate gene polymorphisms associate with the responses found. Differences between African Americans and other racial groups are present with regard to endothelial dysfunction and activation of the renin-angiotensin-aldosterone system. In addition the frequency of polymorphisms of genes involved in the regulation of endothelial function and the renin-angiotensin-aldosterone system differ between African Americans and other ethnic groups. This review highlights the current information available with regard to the genetics of hypertension in African Americans with particular attention to pharmocogenomic studies of antihypertensive therapy.

Nucleoside transporters are a group of poorly understood membrane proteins involved in the movement of nucleoside and many nucleoside analogs across cell membranes. Nucleoside analog drugs are used routinely in various types of chemotherapy. These drugs have been widely used for many years with good results. However, variability in patient response and both de novo and acquired resistance continue to be major obstacles in effective chemotherapy. In combination with the development of new nucleoside analog drugs, a concerted effort is underway to improve our understanding of the genomics and proteomics of nucleoside transporters in order to identify the factors that influence individual patient responses. Here, we describe recent important contributions to our understanding of the genomics and proteomics of this group of proteins with reference to drug bioavailability. In addition, we discuss future approaches, which will provide further insights into nucleoside transporters structure and function.

A DNA microarray is a solid support such as a glass slide, silicon chip or nylon membrane on which DNA molecules are attached at precise locations. Using DNA microarrays, the expression of tens of thousands of genes in a biological sample can be detected in one experiment. Emerging data suggests that the use of DNA microarrays can aid the differentiation of tumors with similar morphological appearance, predict patient outcome independently of conventional prognostic factors and select for response or resistance to specific anti-cancer therapies. DNA microarray technology thus has the potential to supplement standard diagnostic procedures in oncology and permit a more individualized approach to patient management. Prior to clinical application, however, this methodology must be simplified, standardized, evaluated in external quality assessment schemes and made available at relatively low costs. Most importantly, the preliminary, but promising, early findings must be validated by high-level evidence studies, such as large prospective randomized trials or meta-analyses.

Aripiprazole is the first atypical antipsychotic introduced to medical practice with partial dopamine-serotonin agonist properties. Other new molecular entities such as bifeprunox, a partial agonist at the dopamine D2 and serotonin 5- HT1A receptors, are currently being evaluated in early stage drug development as potential antipsychotic agents. As a partial agonist, whether aripiprazole displays an agonist effect or attenuates dopaminergic neurotransmission may depend on regional variations in endogenous dopamine tone. Hence, aripiprazole offers a therapeutic advantage to differentially modulate dopaminergic activity in brain regions in a graded fashion. This mechanism of action is intriguing when considered in the context of the dopamine hypothesis of schizophrenia whereby positive symptoms (e.g. hallucinations and delusions) are associated with increased mesolimbic dopaminergic activity while reduced activity in mesocortical dopaminergic pathways underlies negative symptoms (e.g. avolition and anhedonia) and cognitive deficits. Despite its therapeutic promise, antipsychotic response to aripiprazole is highly variable, and some patients do not respond at all to drug therapy. Treatment-emergent adverse events associated with aripiprazole include insomnia, anxiety, akathisia or worsening of psychosis in some patients. These observations suggest that the underlying mechanism of action of aripiprazole in psychotic disorders is more complex than what would be anticipated solely by simple partial agonist effects at the dopamine D2 receptor. For example, while aripiprazole attenuates dopaminergic hyperactivity it does not increase locomotor activity in reserpinized (hypodopaminergic) rats, which is not fully consistent with a partial agonist mode of action. Aripiprazole can induce a diverse range of effects at dopamine D2 receptors (agonism, antagonism, partial agonism) depending on the cellular milieu defined by promiscuous interactions with a host of signaling partners and variability in local G protein complement and concentration. This diversity provides an opportunity to illustrate the importance of integrating data on genetic variation in pharmacokinetic pathways and molecular targets for antipsychotics including biogenic amine receptors and their downstream signaling partners. Theragnostics, a new subspecialty of molecular medicine formed by combination of therapeutics with diagnostics, offers the potential to synthesize different types of biomarkers (DNA and protein-based) in the context of antipsychotic treatment outcomes. Because the dopamine receptor genetic variation is extensively reviewed elsewhere, we discuss the pharmacogenomic significance of variability in genes encoding for the 5-HT1A (HTR1A) and 5-HT2A (HTR2A) receptors and CYP2D6- and CYP3A4-mediated aripiprazole metabolism. As the field moves toward predictive genetic testing for newer antipsychotics, we emphasize the need for collaboration among pharmacogeneticists, bioethicists and specialists in science and technology studies.

In the last two decades, we have witnessed an exponential growth of our knowledge on cell growth and neoplastic transformation at the molecular level. There is high expectation that these advances will be translated into further improvement in the care of cancer patients, especially in the areas of diagnosis, prognosis and treatment. With the completion of the human genome project and numerous studies on gene expression analyses in lung cancer, our challenge is to understand the tumor morphological changes at the molecular level, which will ultimately lead to novel approaches for patient care. This review will summarize methods for identifying biomarkers of lung cancer and molecular/genetic changes that have been investigated as candidate diagnostic, prognostic and predictive markers for lung cancer. A more concerted and global approach to study the clinical relevance of molecular changes in lung cancers is required in the future.