Application of DNA Microarrays in Pharmacogenomics and Toxicogenomics

Many drugs or xenobiotics can induce specific or nonspecific cellular signal transduction events that activate various physiologic and pharmacologic responses including homeostasis, proliferation, differentiation, apoptosis, and necrosis. To minimize the insults caused by these xenobiotics, tissues and organs are equipped with protective mechanisms that either pump drugs out of the cells (e.g., the multidrug-resistant, mdr, family of proteins) or increase the level of detoxifying enzymes such as phase I and II drug-metabolizing enzymes (DMEs), after exposure to xenobiotics. This review discusses the molecular analysis of pharmaco- or toxicogenomic gene expression profiles following exposure to cancer chemotherapeutic and chemopreventive agents. We present the development of DNA microarray technology and its use in expression profiling of possible signal transduction events elicited by these compounds, and its potential future applications in drug discovery and development in the pharmaceutical industry.     

专题演讲-W1毒理基因组学与蛋白质组学

Pharmacogenomics was established on the fact that certain genetic polymorphisms may cause significantly different responses among individuals exposed to a particular drug. Single nucleotide polymorphism （SNP） is the most common form of genetic polymorphism in human genome.     

Systems Biology: a new hope for drug discovery?

The rapid expansion of biomedical information following the mapping of the human genome has contributed to significant advances in acquiring a highly detailed picture of disease mechanisms at the molecular level. This revolution in biomedical science has also generated hope and expectation for the delivery of novel treatments for serious illnesses. However, the reality is that despite this detailed information the return in terms of delivery of new medicines has been relatively modest.     

Pharmacogenomics: implications and considerations for pharmacists

The Renaissance period of world history is analogous to the renewal of healthcare that will arise from pharmacogenomic discoveries. Just as geography, science, art and communication were reawakened by the works of Columbus, da Vinci, Michelangelo and Gutenberg; genetic science will revitalize the clinical role of pharmacists and generate new interest in pharmacy research and education.     

药物基因组学与不良反应

遗传变异可使个体对药物的反应过于敏感，从而产生严重不良反应。通过检测遗传变异可判断患者是否应避免使用某种药物或调整药物的剂量。     

Applicability of Computational Systems Biology in Toxicology

Systems biology as a research field has emerged within the last few decades. Systems biology, often defined as the antithesis of the reductionist approach, integrates information about individual components of a biological system. In integrative systems biology, large data sets from various sources and databases are used to model and predict effects of chemicals on, for instance, human health. In toxicology, computational systems biology enables identification of important pathways and molecules from large data sets; tasks that can be extremely laborious when performed by a classical literature search. However, computational systems biology offers more advantages than providing a high‐throughput literature search; it may form the basis for establishment of hypotheses on potential links between environmental chemicals and human diseases, which would be very difficult to establish experimentally. This is possible due to the existence of comprehensive databases containing information on networks of human protein–protein interactions and protein–disease associations. Experimentally determined targets of the specific chemical of interest can be fed into these networks to obtain additional information that can be used to establish hypotheses on links between the chemical and human diseases. Such information can also be applied for designing more intelligent animal/cell experiments that can test the established hypotheses. Here, we describe how and why to apply an integrative systems biology method in the hypothesis‐generating phase of toxicological research.     

Pharmacogenomics and drug development

It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.     

Pharmacogenomics and stomach cancer

In subgroups of gastric cancer patients, chemotherapy treatments carry a high risk of toxicity without any clear evidence of antitumor activity. Individualization of therapy is required to treat each patient with the optimal drug and dose. Genetic polymorphisms are the hereditary determinants for interindividual variations of drug effect and the genetic approach represents a new tool to design a tailored therapy. This review focuses on the relevance of the host polymorphisms involved in metabolism, cellular transport and interaction with molecular targets of the drugs used in gastric cancer in conventional or innovative chemotherapy regimens. Pharmacogenetic studies based on a single gene or multi-gene approach (pharmacogenomics) are promising to identify gastric cancer patients at risk for adverse toxicity, but larger and controlled studies are needed to justify changes in the chemotherapeutic strategies.     

药物基因组学与个体化给药

为了促进个体化用药的发展,笔者对药物基因组学的产生以及研究现况进行阐述。发现药物基因组学作为功能基因组学在医药学中的应用,能通过对基因多态性的研究,从根本上促进个体化用药的发展。     

Pharmacogenomics of importance for paclitaxel chemotherapy

Paclitaxel (Taxol) has a broad activity spectrum and is clinically used, often in combination with carboplatin, to treat breast, ovarian and lung cancer. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. However, so far only genetic variants of ABCB1 have been indicated to be associated with response and pharmacokinetics of paclitaxel. Commercially, the patent on paclitaxel has expired; however, from a healthcare perspective, it would be beneficial to identify patients with risk of poor response or high risk of toxicity to reduce hospitalization costs. This article focuses on the pharmacogenomic background for paclitaxel response and interindividual variability.     

高血压的药物基因组学研究与个体化用药

“ 药物治疗学正经历着一场革命，即由经验式治疗向 个体化治疗方向的转变［１］，这给临床药理学研究提供了 难得的机遇和挑战，也是临床药理学工作者面临的普遍 而紧迫的任务［２］。 1药物基因组学研究的临床意义尽管医药生物技术的发展日新月异,新的药物层出不穷,但人类在与疾病作斗争的过程中仍然面临着许多重大难题,如药物疗效个体差异大,总有效率捉摸不定;或药物的不良反应严重,导致巨大的精神和经济损失。临床上可见同种疾病的患者对相同的药物可以产生不同的反应:有人表现出高度敏感性,或容易产生不良反应;有的却表…     

治疗药物监测与药物基因组学

目的将药物基因组学应用到临床合理用药,为临床个体化给药提供依据。方法查阅文献,总结治疗药物监测在临床实践中发现的问题,并阐述药物基因组学等学科的发展与特点。结果基因多态性是药物治疗效果因人而异的最重要因素。通过药物基因组学研究,实现临床个体化药物治疗,是治疗药物浓度监测的进一步延伸和充实。药物基因组学应用到临床合理用药,弥补了以往只根据血药浓度进行个体化给药的不足,也为以前无法解释的药效学现象找到了答案。结论将来的临床药物治疗模式应以遗传药理学、药物基因组学为导向,结合血药浓度监测,来指导特定药物对特定患者的合理使用。