Current Topics in Medicinal Chemistry, Volume 4, No. 13, 2004
Contents
Pharmacogenomics
Guest
Editor: Amadeo M. Parissenti
The Use of DNA
Microarrays to Investigate the Pharmacogenomics of Drug Response in Living
Systems Pp.1327-1343
David J. Villeneuve and Amadeo M. Parissenti
Growth Factor
Signaling and Resistance to Cancer Chemotherapy Pp.1345-1354
Zunyan Dai, Ying Huang and Wolfgang Sadee
Analysis of DNA
Microarray Data Pp.1355-1368
Hubert Hackl, Fatima Sanchez Cabo, Alexander Sturn,
Olaf Wolkenhauer and Zlatko Trajanoski
Stem Cell
Pharmacogenomics Pp.1369-1381
S.A. Bapat and G.C.Mishra
Pharmacogenetics
of Drug Transporters and Its Impact on the Pharmacotherapy Pp.1383-1396
Toshiyuki Sakaeda, Tsutomu Nakamura and Katsuhiko
Okumura
Pharmacogenomics:
The Influence of Genomic Variation on Drug Response Pp.1397-1407
Fabienne J. Thomas, Howard L. McLeod and James W.
Watters
Genotyping as a
Tool to Predict Adverse Drug Reactions Pp.1409-1419
Cuneyt Guzey and Olav Spigset
SNP Discovery
and Typing Technologies for Pharmacogenomics Pp.1421-1429
Richard M. Twyman
The Central
Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology Pp.1431-1452
David W. Moskowitz and Frank E. Johnson
The Regulation
of Pharmacogenomics-based Drugs and Policy Making Pp.1453-1458
Amalia M. Issa
Abstracts
[Back to top] The Use
of DNA Microarrays to Investigate the Pharmacogenomics of Drug Response in Living
Systems
David J. Villeneuve and Amadeo M. Parissenti
With the advent of DNA microarray analysis, it is now possible to examine the response of virtually the entire human genome to cellular drug exposure and to uncover a wide variety of genes correlating with the establishment of drug resistance. This relatively new field of “pharmacogenomics” is likely to vastly increase our understanding of the mechanisms of drug action and how cells respond and adapt to drug exposure. However, DNA microarray studies typically result in the identification of hundreds of genes that may or may not be of relevance in vivo---particularly when large, genetically diverse study populations are used. The challenge to the researcher is to design experimental systems and approaches which minimize variability in the data, increase the reproducibility amongst experiments, allow array data from multiple experiments to be assessed by a variety of statistical, supervised learning, and data clustering approaches, and provide a clear link between drug response and the expression of specific genes. This review provides a description and critical analysis of recent studies on the pharmacogenomics of drug response and discusses current guidelines and approaches for the performance and analysis of DNA microarray experiments in this area.
[Back to top] Growth Factor
Signaling and Resistance to Cancer Chemotherapy
Zunyan Dai, Ying Huang and Wolfgang Sadee
Multiple mechanisms contribute to chemoresistance, eventually leading to failure of cancer chemotherapy. Deregulated growth factor signaling pathways promote cell proliferation and render cancer cells resistant to apoptosis, a common mechanism of chemoresistance. Therefore, inhibitors of growth factor signaling, including antibodies and small molecules, are promising drug candidates for chemotherapy, either given alone or as adjuvants to overcome general drug resistance. While dramatic responses have been attained in some cases, innate or acquired resistance to these novel anticancer drugs is common and limits broad applicability. Treatment failure may arise from complexity of growth factor signaling, with numerous parallel pathways and diverse downstream events. This review discusses the use of pharmacogenomics, assessing multiple growth factor signaling pathways and complex chemoresistance mechanisms. Monitoring expression profiles and activating mutations in growth factor receptors holds promise for the design of individualized therapy with a combination of drugs.
[Back to top] Analysis
of DNA Microarray Data
Hubert Hackl, Fatima Sanchez Cabo, Alexander Sturn,
Olaf Wolkenhauer and Zlatko Trajanoski
Recent advances in DNA microarray technology have great impact on many areas of biomedical research and pharmacogenomics: discovering novel targets and genes, elucidating signatures of complex diseases, transcriptional profiling of models for diseases, and the development of individually optimized drugs based on differential gene expression patterns. Consequently, there is demand for robust methods for data analysis and the choice of adequate statistical tests. This review guides through all steps in the cDNA microarray data analysis pipeline and gives a basic understanding of the challenges in interpreting large microarray datasets.
[Back to top] Stem Cell
Pharmacogenomics
S.A. Bapat and G.C.Mishra
Therapeutic stem cell applications represent a newly evolving approach for the treatment of several genetic and degenerative diseases. The advent of pharmacogenomics too, holds promise for an individualized, optimal treatment regime for a large variety of medical conditions. A combination of the benefits of these two technologies creates a new niche in therapeutic medicine research viz. that of stem cell pharmacogenomics (SCP). The development of this approach requires the application of existing technologies in genomics, proteomics and bioinformatics to resolve the various issues involved in advancing the therapeutic applications of stem cell medicine. In this brief overview of the subject, we attempt to provide fresh insights into the exclusive niche of stem cell pharmacogenomics and discuss some of the priority issues that need to be targeted, based on the existing principles of pharmacogenomics, stem cell characteristics and transplantation medicine. Advances in these areas are imperative in realizing the dream of stem cell therapies contributing towards the improvisation of the quality of human life.
[Back to top] Pharmacogenetics
of Drug Transporters and Its Impact on the Pharmacotherapy
Toshiyuki Sakaeda, Tsutomu Nakamura and Katsuhiko
Okumura
Most drug responses are determined by the interplay of several gene products that influence pharmacokinetics and pharmacodynamics, i.e., drug metabolizing enzymes, drug transporters, and drug targets. With the sequencing of the human genome, it has been estimated that approximately 500-1200 genes code for drug transporters. Concerning the effects of genetic polymorphisms on pharmacotherapy, the best characterized drug transporter is the multidrug resistant transporter P-glycoprotein/MDR1, the gene product of MDR1. Little such information is available on other drug transporters. MDR1 is a glycosylated membrane protein of 170kDa, belonging to the ATP-binding cassette superfamily, and is expressed mainly in intestines, liver, kidneys and brain. A number of various types of structurally unrelated drugs are substrates for MDR1, and their intestinal absorption, hepatobiliary secretion, renal secretion and brain transport are regulated by MDR1. The first investigation on the effects of MDR1 genotypes on pharmacotherapy was reported in 2000: a silent single nucleotide polymorphism (SNP), C3435T in exon 26, was found to be associated with the duodenal expression of MDR1, and thereby the plasma concentration of digoxin after oral administration. At present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical investigations on the association of MDR1 genotypes with the expression and function of MDR1 in tissues, and with pharmacokinetics and pharmacodynamics have mainly focused on C3435T; however, there are still discrepancies in the results, suggesting that the haplotype of the gene should be analyzed instead of a SNP. C3435T is also reported to be a risk factor for a certain class of diseases including the inflammatory bowel diseases, Parkinson’s disease and renal epithelial tumor, and this also might be explained by the effects on MDR1 expression and function. In this review, the latest reports on the effects of genetic polymorphisms of MDR1 on pharmacotherapy are summarized, and the pharmacogenetics of other transporters is briefly introduced.
[Back to top] Pharmacogenomics:
The Influence of Genomic Variation on Drug Response
Fabienne J. Thomas, Howard L. McLeod and James W.
Watters
Unpredictable efficacy and toxicity are major hurdles in the administration of many medications. By identifying inherited DNA polymorphisms that influence drug disposition and effects, pharmacogenomics is an exciting tool for the individualization of drug therapies. Single nucleotide polymorphisms (SNP) in genes encoding drug metabolizing enzymes, drug transporters, and DNA repair genes have recently been shown to influence drug toxicity and efficacy. This review will discuss clinically relevant examples of genetic polymorphisms that influence the outcome of drug therapy, and possibilities for future applications of pharmacogenomics.
[Back to top] Genotyping as a
Tool to Predict Adverse Drug Reactions
Cuneyt Guzey and Olav Spigset
During the last decades, the rapid development in molecular biology has contributed to the understanding of genetic factors underlying many adverse drug reactions. Until recently, most research in this area has focused on genes coding for drug-metabolizing enzymes. Inactivating mutations have been found in genes coding for enzymes belonging to the cytochrome P-450 system, which is the major system for drug metabolism in humans, but also in genes coding for other enzymes. Subjects with a lack of functional activity in these enzymes should be treated with very low doses of drugs metabolized by the same enzyme in order to avoid excessive drug levels and thereby toxic effects.
In the last years, increasing attention has been directed towards genes coding for drug targets. Hitherto, most studies have been carried out on single genes known to be or assumed to be functionally related to a given adverse drug reaction. Another approach, which may become more common in the future, is testing for complex single nucleotide polymorphism patterns that may be associated with adverse drug reactions, although the functional relationship between them may be completely unknown.
Due to the influence of non-genetic factors in the development of adverse drug reactions, the association between a specific genotype and an adverse drug reaction will always be lower than 100%. Therefore, there is a need for prospective large-scale studies in order to elucidate the extent of environmental influences on the adverse drug reactions for which a genetic basis has been suggested. Despite these obstacles, pharmacogenetic testing will hopefully in the future identify at least some clear-cut situations where a drug should be avoided in certain individuals in order to reduce the risk of adverse drug reactions.
[Back to top] SNP Discovery and Typing Technologies for
Pharmacogenomics
Richard M. Twyman
Genetic variation in the human genome occurs predominantly as single nucleotide polymorphisms (SNPs). Our DNA may contain as many as ten million SNPs, of which three million or more are likely to differ between any two unrelated individuals. These three million genetic differences make a significant contribution to the observed variation in complex human phenotypes, such as disease susceptibility and our responses to drugs or environmental chemicals. Largescale association studies taking place throughout the drug development process can help to identify such differences and tailor drugs and dose regimens to particular genotype classes. The need for such large-scale studies has driven the development of high-throughout SNP discovery and typing technologies, which are the subject of this review.
[Back to top] The Central Role of Angiotensin I-Converting
Enzyme in Vertebrate Pathophysiology
David W. Moskowitz and Frank E. Johnson
Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D/D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D/D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the “Cambrian Explosion” in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the “disulfide zipper.” The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.
[Back to top] The Regulation of Pharmacogenomics-based
Drugs and Policy Making
Amalia M. Issa
In addition to potential future clinical benefits such as reducing adverse drug reactions and optimizing therapeutic efficacy, pharmacogenomic applications promise numerous benefits for the pharmaceutical and biotechnology industries, including decreasing the size and expense of clinical trials and streamlining the drug development process. The application of pharmacogenomics and related technological advances to drug development has prompted various regulatory agencies such as the United States Food and Drug Administration to issue guidance documents and other advisory statements. This article delineates the impact of pharmacogenomic-guided drug development on the regulatory process in the United States including relevant highlights of industry guidance documents and policy statements. Hypothetical vignettes are used to illustrate a number of issues that are challenging to policy makers and the potential impact of pharmacogenomic based drug research and development on the regulatory environment.