Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

Purpose  Geldanamycin and its analogues belong to a new class of anticancer agents that inhibit the molecular chaperone heat shock protein 90. We hypothesized that membrane transporters expressed on tumor cells may contribute at least in part to cellular sensitivity to these agents. The purpose of this study is to identify novel transporters as determinant for sensitivity and resistance to geldanamycins. Methods  To facilitate a systematic study of chemosensitivity across multiple geldanamycin analogues, we correlated mRNA expression profiles of majority of transporters with anticancer drug activities in 60 human tumor cell lines (NCI-60). We subsequently validated the gene–drug correlations using cytotoxicity and transport assays. Results  The GA analogues displayed negative correlations with mRNA expression levels of the multidrug resistance protein 1 (MRP1, ABCC1). Suppressing MRP1 efflux using the inhibitor MK-571 and small interfering RNA in cell lines with intrinsic and acquired MRP1 overexpression (A549 and HL-60/ADR) and in cell lines stably transduced with MRP1 (MCF7/MRP1) increased intracellular drug accumulation and increased tumor cell sensitivity to geldanamycin analogues. Conclusions  These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.     

Pharmacogenomics to predict drug response

From theory to proof-of-concept, pharmacogenomics promises to improve future general healthcare in a number of ways. By identifying individuals who will respond to a particular drug treatment compared to those who have a low probability of response, pharmacogenomic test development hopes to aid the physician in prescribing the optimal medication for each patient. This approach promises faster relief from symptoms, a lowering of side effect risks and a reduction in healthcare costs. Pharmacogenomic tests used by the pharmaceutical companies themselves can be used to help identify suitable subjects for clinical trials, aid in interpretation of clinical trial results, find new markets for current products and speed up the development of new treatments and therapies. This type of approach should also see fewer compounds failing during later phases of development. The questions we are faced with as we enter the new millennium, however, are if and when the promises of pharmacogenomnics in improving healthcare will be fulfilled. Currently, there are only a handful of pharmacogenomic tests and associated products which are commercially available and it remains to be seen what impact these will have on the market and on healthcare in general.     

A Train-the-Trainer Approach to a Shared Pharmacogenomics Curriculum for US Colleges and Schools of Pharmacy

Objective. To assess pharmacy faculty trainers’ perceptions of a Web-based train-the-trainer program for PharmGenEd, a shared pharmacogenomics curriculum for health professional students and licensed clinicians.Methods. Pharmacy faculty trainers (n=58, representing 39 colleges and schools of pharmacy in the United States and 1 school from Canada) participated in a train-the-trainer program consisting of up to 9 pharmacogenomics topics. Posttraining survey instruments assessed faculty trainers’ perceptions toward the training program and the likelihood of their adopting the educational materials as part of their institution’s curriculum.Results. Fifty-five percent of faculty trainers reported no prior formal training in pharmacogenomics. There was a significant increase (p<0.001) in self-reported ability to teach pharmacogenomics to pharmacy students after participants viewed the webinar and obtained educational materials. Nearly two-thirds (64%) indicated at least a “good” likelihood of adopting PharmGenEd materials at their institution during the upcoming academic year. More than two-thirds of respondents indicated interest in using PharmGenEd materials to train licensed health professionals, and 95% indicated that they would recommend the program to other pharmacy faculty members.Conclusion. As a result of participating in the train-the-trainer program in pharmacogenomics, faculty member participants gained confidence in teaching pharmacogenomics to their students, and the majority of participants indicated a high likelihood of adopting the program at their institution. A Web-based train-the-trainer model appears to be a feasible strategy for training pharmacy faculty in pharmacogenomics.     

Pharmacogenomics: bench to bedside

Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Since its origins in the mid-twentieth century, a major driving force in pharmacogenetics research has been the promise of individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In recent years, the convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics, and led to increasing enthusiasm for the 'translation' of this evolving discipline into clinical practice. Here, we briefly summarize the development of pharmacogenetics and pharmacogenomics, and then discuss the key factors that have had an influence on - and will continue to affect - the translation of pharmacogenomics from the research bench to the bedside, highlighting the challenges that need to be addressed to achieve this goal.     

Pharmacogenomics and addiction to opiates

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.     

Pharmacogenomics: The implementation phase

Pharmacogenomics makes use of genetic and genomic principles to facilitate drug discovery and development, and to improve drug therapy. Its goal is to attain optimal therapy for the individual patient. This article analyzes current trends in pharmacogenomics and asks how this new science affects drug development in the pharmaceutical industry and the clinical use of drugs.     

Pharmacogenomics

So far no pharmacogenetic/genomic study has been conducted specifically for anxiety disorders. Some of the presented results, however, do pertain to such disorders. For example, pharmacokinetic aspects of antidepressant drug therapy likely also apply to patients with anxiety disorders, and several genetic polymorphisms in the cytochrome P450 (CYP) gene family and drug transporter molecules, such as the multidrug resistance (MDR) gene type 1, have been reported to influence the pharmacokinetics of antidepressant drugs. At this stage of pharmacogenomics research, it is difficult to interpret the relevance of pharmacodynamic-genetic association studies conducted in depressed patients for anxiety disorders. A number of studies have reported an influence of polymorphisms of genes mostly in the serotonergic pathway on the response to antidepressant drugs in patients suffering from depression. In order to know whether they can be extrapolated to patients with anxiety disorders, clinical studies are warranted. Despite all the shortcomings of the currently available pharmacogenetic studies, this field holds great promise for the treatment of anxiety disorders. In the future, psychiatrists may be able to base treatment decisions (i.e., the type and dose of prescribed drug) on more objective parameters than only the diagnostic algorithms used now. This will limit unwanted side effects and adverse drug reactions, and could reduce time to response, resulting in a more individualized pharmacotherapy.     

Pharmacogenomics

Pharmacogenetics is the intersection of the fields of pharmacology and genetics. Simply stated, pharmacogenetics is the study of how genetic variations affect the ways in which people respond to drugs. These variations can manifest themselves as differences in the drug targets or as differences in the enzymes that metabolize drugs. A difference in the target will usually lead to differences in how well the drug works, whereas differences in metabolizing enzymes can result in differences in either efficacy or toxicity. It's also possible that genes not directly involved in a particular pathway could end up being predictive of clinical outcomes. Although pharmacogenomics has the potential to radically change the way health care is provided, it is only in its infancy. In the future, pharmacogenomics could find uses along the entire drug discovery and development timeline, all the way from target discovery and validation to late-stage clinical trials. Beyond that, pharmacogenomics tests could find their way into the doctor's office as a means to get the right medicine to the right patient at the right time. While genetics and genomics are often used synonymously, pharmacogenetics is more focused in scope than and is viewed as a subset of pharmacogenomics, which encompasses factors beyond those that are inherited.     

Pharmacogenomics of platelet responsiveness to aspirin

Aspirin is the most widely used drug in the world for cardiovascular protection. Aspirin's ability to suppress platelet function varies widely among individuals and lesser suppression of platelet function is associated with increased risk of myocardial infarction, stroke and cardiovascular death. Platelet response to aspirin is a complex phenotype involving multiple genes and molecular pathways. Aspirin response phenotypes can be categorized as directly or indirectly related to cyclooxygenase-1 (COX-1) activity, with phenotypic variation indirectly related to COX-1 being much more prominent. Recent data indicate that variability in platelet response to aspirin is genetically determined, but the specific gene variants that contribute to phenotypic variation are not known. An understanding of the relationship between genotype, aspirin response phenotype and clinical outcome will help to bring about a personalized approach to antiplatelet therapy that maximizes antithrombotic benefit whilst minimizing bleeding risk for individual patients.     

Pharmacogenomics: way to individual therapy

Problems pertaining to the development of individual therapy based on the achievements of modern pharmacogenetics and pharmacogenomics, as well as the safety of using drugs from various pharmacological groups in patients belonging to different ethnical groups (with the corresponding features of metabolism) are considered. The terms "pharmacogenetics" and "pharmacogenomics" are discussed in connection to the significance of genetic polymorphism (or single nucleotide polymorphism) in determining of the individual sensitivity with respect to certain drugs.     

药物基因组学基础的药物警戒研究进展

摘要：主要从药物基因组学角度回顾了常见药物的不良反应,特别是严重不良反应,如药物过敏反应,药物心脏、肾脏、肝脏毒性与相关基因的的研究进展,探讨了药物遗传/基因组学技术在药物警戒中的应用现状,并对未来药物遗传/基因组学技术的发展方向及对药物警戒工作的意义作以预测和展望。     

HIV Pharmacogenomics

Pharmacogenomics classically focuses on host nuclear genetic polymorphisms that can be used to predict adverse drug reactions (ADRs). Because ADRs are defined as any noxious, unintended, and undesired drug effects, loss of efficacy due to the development of antiretroviral drug resistance and both acute and cumulative adverse effects of antiretroviral therapy can be considered ADRs. In order to address these types of antiretroviral-associated ADRs, pharmacogenomic testing methods have expanded to include molecular assays that characterize extranuclear genetic material (e.g. HIV and mitochondrial genomes), as well as the host nuclear genetic material. Recent molecular advances permit high resolution resistance testing that detects loss of therapeutic efficacy through the use of phenotypic, genotypic and/or virtual phenotypic resistance testing. These assays use complex technical and interpretative methods to improve the therapeutic efficacy of antiretroviral therapy. The resistance assays demonstrate the utility of pharmacogenomic testing for patients undergoing lifelong and complex antiretroviral therapies. Future applications of antiretroviral-directed pharmacogenomic tests range from quantitative detection of mitochondrial depletion as an early surrogate marker for drug toxicity, to qualitative analysis of host immune haplotypes, and metabolic/transporter genetic polymorphisms for predicting disease progression.In summary, pharmacogenomic testing for HIV-positive patients provides proof of principle that these tests can be used clinically to improve outcomes for patients undergoing complex and sustained drug regimens.     

Pharmacogenomics: The promise of personalized medicine

Pharmacogenetics and pharmacogenomics deal with the genetic basis underlying variable drug response in individual patients. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. On the other hand, pharmacogenomic studies encompass the sum of all genes, i.e., the genome. Numerous genes may play a role in drug response and toxicity, introducing a daunting level of complexity into the search for candidate genes. The high speed and specificity associated with newly emerging genomic technologies enable the search for relevant genes and their variants to include the entire genome. These new technologies have essentially spawned a new discipline, termed pharmacogenomics, which seeks to identify the variant genes affecting the response to drugs in individual patients. Moreover, pharmacogenomic analysis can identify disease susceptibility genes representing potential new drug targets. All of this will lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. Current concepts in drug therapy often attempt treatment of large patient populations as groups, irrespective of the potential for individual, genetically-based differences in drug response. In contrast, pharmacogenomics may help focus effective therapy on smaller patient subpopulations which although demonstrating the same disease phenotype are characterized by distinct genetic profiles. Whether and to what extent this individual, genetics-based approach to medicine results in improved, economically feasible therapy remain to be seen. To exploit these opportunities in genetic medicine, novel technologies will be needed, legal and ethical questions must be clarified, health care professionals must be educated, and the public must be informed about the implications of genetic testing in drug therapy and disease management.     

药物基因组学的应用及其市场前景

目的 :探讨药物基因组学应用前景。方法 :介绍药物基因组学概念 ,分析其应用前景。结果与结论 :药物基因组学应用前景广阔 ,蕴藏着巨大的经济价值 ,对21世纪医药学将产生深远影响。     

药物基因组学，实现个体化给药的核心支柱

为什么患者对药物的疗效与不良反应不一样？ 众所周知，药物治疗的效果因人而异。研究表明，以选择性环氧化酶-2抑制剂为代表的新型抗炎镇痛药的疗效仅为80％，抗抑郁药的有效率为62％，抗哮端药和抗心律失常药分别为60％，抗糖尿病药为57％，抗急性偏头痛药为52％，预防偏头痛药为50％，抗丙型肝炎病毒（HCV）药的有效率为47％，抗尿失禁药为40％，抗阿尔茨海默病药仅为30％，而抗肿瘤药更低，仅为25％；同时，各种药物不良反应的发生率也相差很大，有的人仅仅接触极微量青霉素即发生过敏反应性休克，有的甚至死亡，而更多的人则无不良反应。