Current Pharmacogenomics, Vol. 2, No. 4, 2004
Contents
Novel Approaches for RNA Interference and their
Application in Cancer Therapy Pp.313-324
Joel B. Berletch, Jessica Green, Amanda P. Cunningham,
Lucy G. Andrews and Trygve O.Tollefsbol
Current Chemicals Used for Probing DNA Conformational
Changes and Detection of Unknown Mutations Pp.325-332
Chinh T. Bui, Kylee Rees and Richard G. H. Cotton
Pharmacogenetics, Regulation and Structural Properties of
the Drugmetabolizing Enzymes Arylamine N-acetyltransferases Pp.333-338
Jean-Marie Dupret, Julien Dairou, Noureddine Atmane and
Fernando Rodrigues-Lima
Molecular Biology of Retinitis Pigmentosa: Therapeutic
Implications Pp.339-349
E. Ramon, L.J. del Valle and P. Garriga
Application of Functional Genomics to Bronchial Asthma Pp.351-356
K. Izuhara, K. Arima, N. Yuyama, Y. Sakata, K. Masumoto
Toward a Discipline of Pharmacoepigenomics Pp.357-377
Moshe Szyf
Genetics and Bioenergetics of Mitochondria Influencing
the Etiology and Pharmacology of Steroidal Hormones Pp.379-390
Deodutta Roy, Jai Parkash and Satya Narayan
Abstracts
[Back
to top] Novel Approaches for RNA
Interference and their Application in Cancer Therapy
Joel B. Berletch, Jessica Green, Amanda P. Cunningham, Lucy G. Andrews and Trygve O.Tollefsbol
RNA interference (RNAi) is a phenomenon that has been observed in many species and causes posttranscriptional gene silencing. RNAi targets specific mRNAs for destruction, causing an active gene to be downregulated and in some cases to be knocked out completely in its expression. RNAi technology begins with the introduction of double-stranded RNA (dsRNA) into cells, which initiates a chain reaction of events that ends in the degradation of mRNA that is homologous to the dsRNA. In mammalian systems small interfering RNA (siRNA) of about 21-25 nucleotides must be used to avoid initiating a systemic response intended for defense against viral invasions. Many different methods and vectors have been employed to produce dsRNA and siRNA, which have had varying levels of success. This review addresses the aspects of emerging RNAi technology as well as different approaches used to introduce dsRNAs and siRNAs into cells. RNAi has recently been shown to have promise as a very powerful tool in cancer research, and, potentially, therapy. Recently, much research has been focused on the search for new therapies. Some of the implications of RNAi for therapy and future treatments of cancer are, therefore, also evaluated.
[Back
to top] Current Chemicals Used for Probing DNA
Conformational Changes and Detection of Unknown Mutations
Chinh T. Bui, Kylee Rees and Richard G. H. Cotton
Detection of unknown mutations is a key for success in diagnosis, treatment and therapy of many genetic diseases. Use of chemicals has been practiced for many years to probe the structural changes of DNA induced by a single base mismatch. This paper will review the current chemicals, such as carbodiimides, alkyl halides, aldehydes, oxidants, oxyamines, intercalators and groove binders, which have established the foundation for many useful applications in the areas of genetics and molecular biology.
[Back to top] Pharmacogenetics,
Regulation and Structural Properties of the Drugmetabolizing Enzymes Arylamine N-acetyltransferases
Jean-Marie Dupret, Julien Dairou, Noureddine Atmane and
Fernando Rodrigues-Lima
Xenobiotic-metabolizing enzymes (XME) are responsible for the biotransformation of a vast range of compounds. Arylamine N-acetyltransferases (NAT) are XME responsible for the acetylation of many arylamine and heterocyclic amines. They therefore, play an important role in the detoxification and activation of numerous drugs and carcinogens. Two closely related isoforms (NAT1 and NAT2) have been described in humans. NAT2 is present mainly in the liver and gut whereas NAT1 is found in a wide range of tissues. Interindividual variations in NAT genes have been shown to be a potential source of pharmacological and/or pathological susceptibility. In addition, there is now evidence that non genetic factors, such as substrate-dependent inhibition or redox conditions, may also contribute to overall NAT1 activity. This mini-review summarizes current knowledge on human NATs. Recent aspects of NAT gene expression, regulation and structural properties are discussed.
[Back
to top] Molecular Biology of Retinitis Pigmentosa: Therapeutic
Implications
E. Ramon, L.J. del Valle and P. Garriga
Retinitis pigmentosa is a group of retinodegenerative diseases caused by mutations or deletions in over one hundred different genes. These mutations ultimately lead to blindness of those affected by the disease. A number of therapeutic approaches are currently under study and these are primarily directed to block or, if possible, to revert the effects of the mutations that cause photoreceptor cell apoptosis. A therapy that could only slow down the progression of the disease would be regarded as a major success especially if we take into account that there is no effective therapy at present.
Recent advances in molecular biology and genetics have opened the pace for promising molecular and cellular approaches aimed at fighting against the progression of the retinal degenerative process. These include using encapsulated cells containing neurotrophic factors that can be released into the eye in a controlled manner, ribozyme techniques directed towards specific degradation of mutated RNAs, and stem cell differentiation into photoreceptor cells for transplantation to the affected retina, among others. Different research lines in the gene therapy field are also being developed. Those targeting the apoptotic pathway are among the most studied and are included in the therapeutic strategies that can have a broader impact because they may be independent on the specific gene mutated. In any case a future is foreseen when these approaches, based on molecular genetic knowledge, can lead to individualized treatment for different patients carrying different mutations, or different treatments for the same patient at different stages of the disease.
[Back
to top] Application of Functional Genomics to
Bronchial Asthma
K. Izuhara, K. Arima, N. Yuyama, Y. Sakata, K. Masumoto
Bronchial asthma is a complicated and diverse disorder affected by genetic and environmental factors. It is widely accepted that it is a Th2-type inflammation originating in lung and caused by inhalation of ubiquitous allergens. The complicated and diverse pathogenesis of this disease is yet to be clarified. Functional genomics is the analysis of whole gene expression profiling under given condition, and microarray technology is now the most powerful tool for functional genomics. Several attempts to clarify the pathogenesis of bronchial asthma have been carried out using microarray technology, providing us some novel pathogenic mechanisms of bronchial asthma as well as the information of gene expression profiling. In this article, we review the outcomes of these analyses by the microarray approach as applied to bronchial asthma.
[Back
to top] Toward a Discipline of Pharmacoepigenomics
Moshe Szyf
This review argues that the epigenome, which plays a critical role in controlling gene expression, plays also an important role in drug responsiveness. The epigenome is composed of chromatin and its modifications and DNA methylation. DNA methylation and chromatin structure are dynamic and tightly linked. Alterations in DNA methylation are involved in the pathology of cancer and in normal aging. It is suggested here that pharmacoepigenomics should be recognized as a new field in pharmacology. This field will address the epigenomic basis of issues which were traditionally the focus of pharmacogenetics and pharmacogenomics such as inter-individual differences in drug responsiveness, the impact of drugs on gene expression profiles, identification of unpredicted side effects of drugs at early stages of preclinical development and the discovery of novel drug targets. The reversibility of epigenetic states presents therapeutic and prophylactic opportunities, which necessitate the development of drugs that target the epigenomic machinery. Such drugs might be of therapeutic value in cancer and other diseases and in promoting and altering drug responsiveness.
[Back
to top] Genetics and Bioenergetics of Mitochondria
Influencing the Etiology and Pharmacology of Steroidal Hormones
Deodutta Roy, Jai Parkash and Satya Narayan
Mitochondria are important targets of steroid hormone action. The receptors for steroid hormones, including estrogen, thyroxine and glucocorticoid, are present in the mitochondria, while steroid hormone responsive elements are also found in the mitochondrial genome. The presence of the steroid hormone receptors in the mitochondria, transport of ligands to the mitochondria, sequences of hormone response elements in the mitochondrial genome, and modulation of mitochondrial encoded genes by steroid hormones support a direct action of steroid hormones on mitochondrial gene transcription. This is parallel to the primary actions of the steroid hormones on nuclear gene transcription as a mechanism to coordinate regulation of mitochondrial biogenesis by steroid hormones. The cross-talk between the cell nucleus and the mitochondria appears to control steroid hormone-induced signaling involved in the apoptosis, proliferation, and differentiation of both normal and malignant cells. Evaluation of the defects in genetics and physiology of mitochondria, specifically in steroids hormone-related endocrine diseases in humans, suggests that several variants of human endocrine diseases, including cancer, manifest as a result of mitochondrial physiologic and metabolic compensation of genetic defects. The steroidal agents control biogenesis and maintenance of mitochondria through the crosstalk between nuclear and mitochondrial genomes. The regulation of mitochondrial transcription by steroidal hormones, presumably occurring through pathways similar to those that take place in the nucleus, opens a new way to better understand steroid hormone and vitamin action at the cellular level. Therefore, an in-depth analysis of such regulatory mechanisms is pertinent to the development of novel drugs and gene therapy strategies for the treatment of steroid hormone-dependent diseases related to mitochondrial disorders including cancer.