摘要:

Drug treatment of psychiatric disorders is troubled by severe adverse effects, low compliance and lack of efficacy in about 30% of patients. Pharmacogenetic research in psychiatry aims to elucidate the reasons for treatment failure and adverse reactions. Genetic variations in cytochrome P450 (CYP) enzymes have the potential to directly influence the efficacy and tolerability of commonly used antipsychotic and antidepressant drugs. The activity of psychiatric drugs can also be influenced by genetic alterations affecting the drug target molecule. These include the dopaminergic and serotinergic receptors, neurotransmitter transporters and other receptors and enzymes involved in psychiatric disorders. Association studies investigating the relation between genetic polymorphisms in metabolic enzymes and neurotransmitter receptors on psychiatric treatment outcome provide a step towards the individualization of psychiatric treatment through enabling the selection of the most beneficial drug according to the individual's genetic background.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Osteoporosis, which afflicts 10 million Americans, is a complex disease characterized by decreased bone mass, microarchitectural deterioration of bone tissue, and an increase in fracture risk. Family and twin studies have established a genetic contribution to the etiology of osteoporosis. The biological candidate genes of osteoporosis can be ordered into 5 categories: (i) calcium homeostasis; (ii) hormonal dysfunction; (iii) osteoblast and osteoclast development and regulation; (vi) cartilage matrix metabolism; and (v) lipoprotein metabolism. In addition, genome-wide scans have identified a number of chromosomal regions harboring genes that influence bone mineral density. Moreover, the drug responses to various treatments of osteoporosis are reported to be modulated by DNA polymorphisms of the vitamin D receptor gene, the estrogen receptor 1 gene, and the transforming growth factor β1 gene. With the rapid advancement of the Human Genome Project and biotechnology, it will be possible to carry out parallel analyses of large numbers of candidate genes for osteoporosis and to calculate a patient's individual fracture risk in the context of specific environmental influences. This will eventually lead to more advanced diagnostic methods and more efficacious drugs targeting osteoporosis.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

It is now well established that non-Mendelian examples of DNA instability are associated with human disease. Most malignancies are associated with various chromosomal instabilities, such as aneuploidy, gene amplification, and chromosomal deletion. Furthermore, widespread microsatellite instability (MSI) is associated with a variety of tumors, and instability at specific dynamic repeat expansions underlies a family of neurologic disorders. Inactivation of DNA mismatch repair genes results in genomic instabilities affecting microsatellite regions. Mutations in genes involved in DNA polymerization or Okazaki fragment processing are also associated with MSI. Such instabilities convey a ‘mutator’ phenotype which is pathogenic. The mechanisms controlling trinucleotide repeat expansions are less well understood. Why this type of genomic instability is particularly pathogenic to neurons is also not clear. An understanding of what normally maintains stability is the first step towards preventing such loss of control and maintaining health.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

As an increasing number of available genomes triggers a gold rush in modern biology, the scientific challenge shifts towards understanding the total of the encoded information, most notably the proteins, their structures, functions and interactions. Currently this work is in its early stages but the near future will bring a merger of biology, engineering and informatics with a far broader impact on society than pure genomics has had so far. The challenge of characterizing the structures and functions of all proteins in a given cell demands technological advances beyond the classical methodologies of protein biochemistry. Mass spectrometry techniques for high-throughput protein identification, including peptide mass fingerprinting, sequence tagging and mass spectrometry on full-length proteins are providing the driving force behind proteomics endeavors. New technologies are needed to move high-resolution protein structure determination to an industrial scale. Nonetheless, improvements in techniques for the separation of intrinsic membrane proteins are enabling proteomics efforts towards identifying drug targets within this important class of biomolecules. Beyond the acquisition of data on sequences, structures and interactions, however, the major work in drug discovery remains: the screening of large candidate compound libraries combined with clever medicinal chemistry that guarantees selective action and defined delivery of the drug.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The human genome is sequenced, but only a minority of genes have been assigned a function. Whole-genome expression profiling is an important tool for functional genomic studies. Automated technology allows high-throughput gene activity monitoring by analysis of complex expression patterns, resulting in fingerprints of diseased versus normal or developmentally distinct tissues. Differential gene expression can be most efficiently monitored by DNA hybridization on arrays of oligonucleotides or cDNA clones. Starting from high-density filter membranes, cDNA microarrays have recently been devised in chip format. We have shown that the same cDNA libraries can be used for high-throughput protein expression and antibody screening on high-density filters and microarrays. These libraries connect recombinant proteins to clones identified by DNA hybridization or sequencing, hence creating a direct link between gene catalogues and functional catalogues. Microarrays can now be used to go from an individual clone to a specific gene and its protein product. Clone libraries become amenable to database integration including all steps from DNA sequencing to functional assays of gene products.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The nematodeCaenorhabditis elegansis the first multicellular organism with a fully sequenced genome. As a model organism,C. elegansis playing a special role in functional genomic analyses because it is experimentally tractable on many levels. Moreover, the lessons learned fromC. elegansare often applicable across phyla because many of the key biologic processes involved in development and disease have been well conserved. Many global approaches for analysing gene activity are being pursued inC. elegans.RNA-mediated interference (RNAi) is an efficient high-throughput method to disrupt gene function. The basic technique of RNAi involves introducing sequence-specific double-stranded RNA intoC. elegansin order to generate a nonheritable, epigenetic knockout of gene function that phenocopies a null mutation in the targeted gene. This technique drastically reduces the time needed to jump from the identification of an interesting gene sequence to achieving an understanding of its function. Thus, RNAi facilitates the high-throughput functional analysis of gene targets identified during drug discovery. RNAi can also help to identify the biochemical mode of action of a drug or pesticide and to identify other genes encoding products that may respond or interact with specific compounds.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Cardiovascular disease is the leading cause of mortality and morbidity in developed countries. Most conventional therapy is often inefficacious and tends to treat the symptoms rather than the underlying causes of the disorder. Gene therapy offers a novel approach for prevention and treatment of cardiovascular diseases. Technical advances in viral vector systems and the development of fusigenic liposome vectors have been crucial to the development of effective gene therapy strategies directed at the vasculature and myocardium in animal models. Gene transfer techniques are being evaluated as potential treatment alternatives for both genetic (familial hypercholesterolemia) and acquired occlusive vascular diseases (atherosclerosis, restinosis, arterial thrombosis) as well as for cardiac disorders including heart failure, myocardial ischemia, graft coronary arteriosclerosis and hypertension. Continued technologic advances in vector systems and promising results in human and animal gene transfer studies make the use of gene therapy a promising strategy for the treatment of cardiovascular disorders.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

DNA acts as the final target for most clinically effective cytotoxic agents, but the lack of selectivity for tumor cells has raised questions about the value of developing new DNA-interactive agents. Three new classes of cytotoxic agents are reviewed; each interacts directly with DNA but cytotoxicity appears to be mediated through novel mechanisms, including the interaction with specific proteins by DNA-bound drug molecules.Irofulven is the lead compound of the illudin family of molecules. It causes a novel type of DNA damage whose repair is dependent on functioning DNA helicases. Pre-clinical and clinical synergy between irofulven and agents which inhibit topoisomerases has been observed. Clinical trials with irofulven have shown significant activity and phase II studies in pancreatic, ovarian and prostatic cancer are ongoing. Toxicity in the form of myelosuppression and fatigue have been shown to be schedule dependent, with intermittent administration appearing to significantly reduce toxicity.DNA-interacting agents which alkylate bases exposed in the minor groove have been derived from a number of natural sources. The minor groove alkylation appears to be sequence specific; although the significance of this specificity for cytotoxicity is unclear, one proposed mechanism is through inhibition of expression of particular genes. Three cyclopropylpyrroloinole analogues which cause sequence specific minor groove alkylation are currently under clinical assessment. Myelosuppression is the dose limiting toxicity and is biphasic in its time course. Moderate activity in phase I trials has been observed.Ecteinascidins represent one of the increasing number of groups of drugs isolated from marine organisms. Ecteinascidin-743 (ET-743) is the most advanced in its clinical development. Binding to the minor groove of DNA occurs, although with a different base specificity from other compounds. The cytotoxic effects of ET-743 may occur by inhibition of the inducible transcription of a number of genes by sequestration of specific transcription factors. Clinical trials of ET-743 have shown significant activity, and phase II trials are underway in soft tissue sarcoma and breast cancer. Hepatic toxicity and myelosuppression are predictable and appear associated with peak plasma concentrations, whereas efficacy seems to be improved with prolonged infusion.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS