摘要:

The prognosis of patients with colorectal cancer is impacted by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Optimal postoperative management of patients who have undergone successful tumor resection involves the utilization of reliable determninants of prognosis to help select patients who would benefit from adjuvant treatment, while sparing others from drug-related adverse effects. Tailoring chemotherapy for patients with disseminated cancer, or for patients who receive adjuvant chemotherapy, is also critical.Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets, and drug transport molecules is an important contributing factor. The identification of genetic markers of response and prognosis will aid in the development of more individualized chemotherapuetic strategies for cancer patients. Potential prognostic indicators in colorectal cancer include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, molecular markers such as deletion of 18q (DCC), p27 and microsatellite instability are promising as indicators of good or poor prognosis.Molecular determinants of efficacy and host toxicity of the most commonly used drugs in colorectal cancer, fluoracil, irinotecan and oxaliplatin, are being investigated. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, dUTP nucleotidehydrolase and thymidine phosphorylase (for fluoropyrimidine-based chemotherapy), uridine diphosphate glucosyltransferase (UGT) 1A1 and carboxylesterase (for irinotecan therapy), and excision repair cross-complementing genes (ERCC1andERCC2) and glutathione-S-transferase P1 (for oxalilplatin-based regimens) may be useful as markers for clinical drug response, survival and host toxicity.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The pathogenetic mechanism of neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect of antipsychotics, is not well understood. In addition to acquired risk factors, clinical observations suggest a number of genetic factors predisposing patients to NMS. Recent findings in pharmacogenetics indicate that the genetic polymorphisms for drug-metabolizing enzymes, drug transporters, and possibly drug-targeting molecules, are associated with the interindividual differences in drug responses concerning both efficacy and adverse reactions.Genetic association studies have sought to identify polymorphisms influencing susceptibility to NMS, especially with respect to the dopamine D2receptor, serotonin receptor, and cytochrome P450 2D6. While a few candidate polymorphisms were associated with NMS, a large controlled study is needed to attain statistical power. On the other hand, NMS might include heterogeneous conditions with common characteristic symptoms but different causative mechanisms.Further analysis of individuals with identified genetic mutations or polymorphisms should advance our understanding of mechanisms underlying NMS.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The human genome project, as well as advances in our understanding of asthma susceptibility, are yielding novel candidate targets for disease intervention. The normalization of up-regulated gene expression may treat or improve the disease outcome. However, only some of these gene product targets may be ‘tractable’, i.e. amenable to blockade by small, orally active, organic molecules. The remainder have been termed ‘non-tractable’.For over a decade, antisense oligonucleotides (ASONs) have been used as tools to evaluate the importance of specific gene productsin vitro. In recent years evidence has accumulated indicating their potential as a viable new therapeutic approach in their own right, being able to block ‘non-tractable’ targets as well as ‘tractable’ targets.Distribution, cell-specific uptake, and effectiveness of aerosolized phosphorothioate ASONs are currently being evaluated in animal models. The results demonstrate broad distribution throughout the lung, and uptake by all of the cell types examined to date. Functionality has been demonstrated against diverse targets, including nuclear transcription factors, tyrosine kinases, G-protein coupled receptors, cytokine receptors, growth factors, and chemokines.EPI-2010, a respirable ASON (RASON) against the adenosine A1receptor, is the first test case for this new class of respiratory therapeutics. The rationale for EPI-2010 is that overactivity of the adenosine-signaling pathway in asthmatic lungs contributes to airway inflammation and hyperresponsiveness. EPI-2010 binds to the initiation codon of the adenosine A1receptor mRNA, and thereby blocks translation and targets the message for degradation by RNase. EPI-2010 is apparently metabolized locally by endogenous nucleases confining its activity to the airways. Phase I clinical trials have shown EPI-2010 to be well-tolerated, with indications of efficacy.In conclusion, one important application of RASONs is in addressing up-regulated disease targets, only some of which are ‘tractable’ by small molecules. It is hoped that this will yield new therapeutic options to the benefit of patients with asthma and allergic disorders.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Better than gene sequencing or quantitative amplification, proteomics tools allow the study of tumor phenotype. Indeed, most current prognostic tests in cancer (carcinoembryonary antigen [CEA], prostate-specific antigen [PSA], CA 19-1, CA 125, alpha-fetoprotein [AFP], etc.) are based on the detection and quantification of single proteins in body fluids. However, a common characteristic of these tests is their relatively low predictive value, so that they are usually complemented with other procedures such as biopsy and/or endoscopy. Recently, improved analytical and bioinformatics tools have driven the attention on pattern recognition approaches rather then single-marker tests for prognostic forecasting. It is expected that predicting metastasization on the basis of tumoral protein patterns will soon be a reality. However, currently available technologies either limit the number of proteins that can be analyzed simultaneously or they are expensive, difficult, and time-consuming. Moreover, the tools adapted for expression proteomics might not be the same as those for prognostic studies that require investigation of protein function over time. We believe that clinical proteomics research designed within a precise clinical and pathology framework should be strongly supported, since many prognostic factors are determined not by the tumor itself, but by the patient, the treatment and the environment.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Nociceptin/orphanin FQ (noc/oFQ) is the first novel bioactive substance to have been discovered by the implementation of a functional genomics/reverse pharmacology approach. The neuropeptide was indeed identified in brain extracts as the natural ligand of a previously cloned orphan G protein-coupled receptor, the opioid receptor-like 1 (ORL1) receptor.Since its discovery in 1995, noc/oFQ has been the subject of intensive study to establish its role in normal brain function and its possible involvement in neurophysiopathology. Although the neuropeptide, an inhibitor of neuronal activity, has been found to have a wide spectrum of pharmacological effectsin vivo, none has been as intensively investigated as its action on nociception and nociceptive processing. There is now substantial evidence that noc/oFQ has a modulatory role in nociception. However, dependent on the dose and site of injection, and possibly the animal’s genetic background and even psychological status, the peptide has been variously reported to cause allodynia, hyperalgesia, analgesia, and even pain, in rodents.Overall, noc/oFQ tends to facilitate pain when administered supraspinally, and to inhibit it when administered spinally. These opposing effects beg the obvious, yet still unanswered, question as to what would be the net effect on nociception of an ORL1 receptor ligand, agonist or antagonist, able to target supraspinal and spinal sites simultaneously. Owing to the research effort of several drug companies, such ligands, i.e. nonpeptidic, brain-penetrating agonists and antagonists, have recently been produced whose systematic screening in animal models of acute and inflammatory pain may help validate the ORL1 receptor as the target for novel, non-opioid analgesics.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Since the fundamental discovery that RNA catalyzes critical biological reactions, the conceptual and practical utility of nucleic acid catalysts as molecular therapeutic and diagnostic agents continually develops. RNA and DNA catalysts are particularly attractive tools for drug discovery and design due to their relative ease of synthesis and tractable rational design features. Such catalysts can intervene in cellular or viral gene expression by effectively destroying virtually any target RNA, repairing messenger RNAs derived from mutant genes, or directly disrupting target genes. Consequently, catalytic nucleic acids are apt tools for dissecting gene function and for effecting gene pharmacogenomic strategies. It is in this capacity that RNA and DNA catalysts have been most widely utilized to affect gene expression of medically relevant targets associated with various disease states, where a number of such catalysts are presently being evaluated in clinical trials. Additionally, biotechnological prospects for catalytic nucleic acids are seemingly unlimited. Controllable nucleic acid catalysts, termed allosteric ribozymes or deoxyribozymes, form the basis of effector or ligand-dependent molecular switches and sensors. Allosteric nucleic acid catalysts promise to be useful tools for detecting and scrutinizing the function of specified components of the metabolome, proteome, transcriptome, and genome. The remarkable versatility of nucleic acid catalysis is thus the fountainhead for wide-ranging applications of ribozymes and deoxyribozymes in biomedical and biotechnological research.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

BackgroundAmericans of African ancestry are less likely to receive a selective serotonin reuptake inhibitor (SSRI) for treatment of major depressive disorder than Americans of European ancestry. A functional insertion/deletion polymorphism in the promoter of the serotonin transporter (5-HTT) geneSLC6A4has been shown to modulateSLC6A4transcription, affecting response to SSRIs. Several studies in populations of predominantly European ancestry have consistently found that theSLC6A4promoter polymorphism (referred to as the 5-HTT-linked polymorphic region; 5-HTTLPR) long (L) allele is associated with better response to SSRI treatment than the short (S) allele.ObjectiveThe frequency ofSLC6A4(5-HTTLPR) alleles in 865 black Americans and Afro-Caribbeans was examined to assess possible implications for treatment.Study design and methodsSLC6A4(5-HTTLPR) genotypes were determined in individuals with self-identified African ancestry from South Carolina (n = 489), western Pennsylvania (n = 207), and Tobago (n = 169). Frequencies were compared using chi-square analyses.ResultsIt was verified that the L allele is highly prevalent in Americans of African ancestry, ranging from 77% in western Pennsylvania to 87% in South Carolina. The frequency of theSLC6A4-(L) allele is significantly higher in African-Americans than has been reported for European-Americans (typically 56–60%). There are both statistically significant geographic differences and slight deviations from Hardy-Weinberg equilibrium.ConclusionsGiven the potential influence on treatment response, these findings have implications for the use of SSRIs in this population. The results suggest that additional studies to examine the impact of these alleles on treatment response in African-Americans are warranted.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS