摘要:

Ovarian cancer is the leading cause of death from gynecologic malignancies among American women and the fourth most frequent cause of death from cancer in women in Europe and the US. Despite appropriate surgical and chemotherapeutic intervention, the 5-year survival in patients with metastatic cancer remains poor. Currently available screening methods, including CA125, additional biomarkers, and transvaginal ultrasound lack the necessary sensitivity and specificity to provide accurate and cost-efficient screening for the general population or the ability to assess who will benefit most from each treatment. These limitations have prompted the study of proteomic technology and its application in ovarian cancer diagnostics.Proteomics is the study of molecules in the functional protein pathways of normal or diseased states. Clinical trials are currently being conducted to assess the sensitivity and specificity of serum proteomic patterns and additional clinical trials are designed to evaluate the effects of molecularly targeted agents on protein signaling pathways in human subjects. Overcoming both scientific and practical limitations will lead to increased knowledge of deranged protein networks in cancer cells. Clinical trials in proteomics may result in improved early detection, better monitoring, new drugs and molecularly targeted therapeutics, and individualized therapies.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders.There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2,DRD3, andDRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role ofDRD1, NMDA receptor genes (GRIN1,GRIN2A,GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN),BDNF, and theDRD2promoters confer susceptibility to clinical psychiatric conditions.Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles ofDRD2and the hyperactive alleles ofCOMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

The economic hurdles of drug development and the emergence of genomic technologies such as chemogenomics are combining to shift the existing paradigms in preclinical drug development. Today, the information gleaned from high content molecular data has begun to augment traditional approaches to the assessment of drug safety. The optimal approach is a hybrid strategy employing chemogenomic data and gene expression-based biomarkers of drug efficacy and toxicity to supplement low content and insensitive methods for risk assessment and mechanistic evaluation of drug candidates. Large reference databases of chemogenomic data are essential to the derivation and validation of accurate and predictive gene expression biomarkers. An example of the development of a predictive biomarker for hepatic bile duct hyperplasia is described herein.As gene expression technologies improve, biomarkers will achieve higher throughput, and become more cost effective and increasingly accurate. This will elevate the value of chemogenomics in drug development, shift attrition to earlier in the process, and reduce the overall cost of drug development. Over the past 2 to 3 years, the transition of chemogenomics from a research tool to a decision-making tool has begun and regulatory agencies are anxiously awaiting implementation of this technology to make faster and more informed evaluations of potential drugs.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

In the past 10 years, progress made in cancer biology, genetics, and biotechnology has led to a major transition in cancer drug design and development. There has been a change from an emphasis on non-specific, cytotoxic agents to specific, molecular-based therapeutics.Mechanism-based therapy is designed to act on cellular and molecular targets that are causally involved in the formation, growth, and progression of human cancers. These agents, which may have greater selectivity for cancer versus normal cells, and which may produce better anti-tumor efficacy and lower host toxicity, can be small molecules, natural or engineered peptides, proteins, antibodies, or synthetic nucleic acids (e.g. antisense oligonucleotides, ribozymes, and siRNAs). Novel targets are identified and validated by state-of-the-art approaches, including high-throughput screening, combinatorial chemistry, and gene expression arrays, which increase the speed and efficiency of drug discovery and development. Examples of oncogene-based, molecular therapeutics that show promising clinical activity include trastuzumab (Herceptin®), imatinib (Gleevec®), and gefitinib (Iressa®).However, the full potential of oncogenes as novel targets for cancer therapy has not been realized and many challenges remain, from the validation of novel targets, to the design of specific agents, to the evaluation of these agents in both preclinical and clinical settings. In maximizing the benefits of molecular therapeutics in monotherapy or combination therapy of cancer, it is necessary to have an understanding of the underlying molecular abnormalities and mechanisms involved.This is the first part of a four-part review in which we discuss progress made in the last decade as it relates to the discovery of novel oncogenes and signal transduction pathways, in the context of their potential as targets for cancer therapy. This part delineates the latest discoveries about the potential use of growth factors and protein tyrosine kinases as targets for therapy. Later parts focus on intermediate signaling pathways, transcription factors, and proteins involved in cell cycle, DNA damage, and apoptotic pathways.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveThe aim of this study was to address the presently controversial question of whether cytochrome P450 (CYP) 3A5 polymorphism is associated with hypertension.MethodWe studied 373 elderly (age ≥75 years) Finnish (Caucasian) patients from the ongoing DEBATE (Drugs and Evidence Based Medicine in the Elderly) trial. The patients were classified into those with a history of hypertension (n = 229) and those without a history of hypertension (n = 144) on the basis of a detailed questionnaire on each patient’s medical history and an interview. The patients were genotyped for theCYP3A56986A/G single nucleotide polymorphism (SNP) [CYP3A5*1/*3 alleles].ResultsThe proportion of individuals with theCYP3A5*1/*3 genotype, i.e. CYP3A5 expressors, was significantly higher among patients with a diagnosis of hypertension than among patients without (18.3% vs 9.0%, p = 0.016). The corresponding odds ratio was 2.26 (95% CI 1.17, 4.38). The allele and genotype frequencies for the two control SNPs,ABCB1(MDR1) 3435C/T andSLCO1B1521T/C, did not differ between the two groups.ConclusionThis work lends support to the theory that the polymorphic CYP3A5 enzyme may be involved in regulation of blood pressure. The possible role ofCYP3A5as a genetic contributor to hypertension susceptibility warrants further study.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundData analytic approaches to Affymetrix®microarray data include: (a) a covariate model, in which the observed signal is some estimated linear function of perfect match (PM) and mismatch (MM) signals; (b) a difference model [PM-MM]; and (c) a PM-only model, in which MM data is not utilized.MethodsBy decomposing the correlations among the variables in the statistical model and making certain assumptions, we theoretically derive the statistical model that reflects the actual gene expression level under a variety of conditions expected in microarray data.Results and conclusionWhen modeling non-systematic variation, the covariate model provides maximum flexibility and often reflects the actual gene expression levels better than the difference model. However, the PM-only model demonstrates superior power in an overwhelming majority of realistic situations, which provides theoretical support for the current trend to employ PM-only models in microarray data analyzes.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS