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PubMed2005

The role of transcriptome analysis in pre-clinical toxicology.

A major benefit of the genomics revolution in biomedical research has been the establishment of transcriptome analysis as an enabling technology in the drug development process. Nowhere in the realm of drug development has the expectation of the impact of transcriptome analysis been greater than in the area of pre-clinical toxicology. Transcriptome analysis, along with other new high-content data generating technologies, has the potential to radically improve the drug safety assessment process by allowing drug development teams to identify potential toxicity liabilities earlier, and thus proceed only with those molecules that have both efficacy at the target and a low potential for toxicity in the human population. In this review we will briefly describe the major ways in which transcriptome analysis is being applied in the pre-clinical safety assessment process, focusing primarily on four areas where transcriptome analysis has already begun to have impact. These include using transcriptome analysis to: 1) understand mechanisms of toxicity: 2) predict toxicity: 3) develop in vivo and in vitro surrogate models and screens; and, 4) develop toxicity biomarkers. We will close by briefly addressing future trends and needs in the application of transcriptome analysis to drug safety assessment.

Amyloid Precursor Protein Secretases↗
PubMed2005

DNA microarrays in clinical cancer research.

The recent sequencing of the human genome, coupled with advances in biotechnology, is enabling the comprehensive molecular "profiling" of human tissues. In particular, DNA microarrays are powerful tools for obtaining global views of human tumor gene expression. Complex information from tumor "expression profiling" studies can, in turn, be used to create novel molecular cancer diagnostics. We discuss the utility of DNA microarray-based tumor profiling in clinical cancer research, highlight some important recent studies, and identify future avenues of research in this evolving field.

Biomarkers, Tumor↗
PubMed2005

Toxicogenomics of cationic lipid-based vectors for gene therapy: impact of microarray technology.

Implementation of the high-throughput microarray gene expression profiling technology towards "toxicogenomics" has advanced identification process for safer drugs in the century of 'omics' technology. Applying such technology, in fact, to identify mechanisms for cellular toxicity can provide a means to clarify safety liabilities early in the drug discovery and developments process. The underlying principle in gene therapy is primarily targeting a specific gene (e.g., for silencing). Hence, massive efforts have been devoted to validate the gene-based therapeutics, regardless of toxicogenomics potential of delivery systems. Of the gene delivery systems, viral and non-viral vectors, as two main paradigms, have so far been widely used for delivering of the genome-based therapeutics such as oligonucleotide, small interfering RNA and DNA. However, the use of viral vectors was narrowed due to the safety concerns. Non-viral vectors were utilized as safer alternatives for gene delivery in vitro and ex-vivo; though their success for in vivo gene therapy has been limited due to low efficiency and safety issues. Fundamental principle for gene therapy is to deliver gene-based therapeutics into target cells for specific gene targeting ideally with minimal cellular toxicity. Until now, few works have been conducted about geno-compatibility of delivery systems itself, including cationic lipid-based nanosystems. Inadvertent toxicogenomic impact of gene delivery systems (e.g., cationic lipids) may intrinsically affect the outcome of gene therapy, where often only a single desired genetic change is sought. Further, there exists a possibility that gene changes induced by the lipid delivery system itself could exacerbate, attenuate or even mask the desired effects of the gene-based therapeutics. This review will focus on toxicogenomics impact of the cationic lipid-based formulations for gene therapy.

Animals↗
PubMed2005

Large-scale databases in toxicogenomics.

The use of genomics to improve molecular strategies in safety assessment has immense promise, with increased mechanistic understanding and improved prediction of unknown compounds possible. Several public initiatives in toxicogenomics are now underway, and mechanistic findings are clearly emerging. A number of databases and standards are emerging to support these initiatives. Significant attention to standardization, both for biologic and technical issues, will be necessary for effective community database(s) to be fully operational.

Animals↗
PubMed2006

Development of a toxicogenomics in vitro assay for the efficient characterization of compounds.

In vitro toxicogenomics represents a useful approach for evaluating the toxic properties of new drug candidates early in the drug discovery process using minimal amounts of compounds. The aim of this study was to develop in vitro-based gene expression assays for two prototypical toxicological classes: aryl hydrocarbon receptor (AhR) agonists and peroxisome proliferator activated receptor alpha (PPAR alpha) agonists. Primary rat hepatocytes were exposed to a number of class-specific compounds, including 3-methylcholanthrene, aroclor, and beta-napthoflavone as AhR agonists, bezafibrate, clofibrate, and Wy-14643 as peroxisome proliferators, and chlorpheniramine, penicillin and spectinomycin as negative controls. Global gene expression profiles were generated with microarrays for each class of compounds. Using linear discriminant analysis coupled with permutation-based t-test, gene signatures were established to classify compounds according to a discriminant score. The final gene signatures consist of eight genes for AhR agonism and 11 genes for PPAR alpha agonism, and were further validated using additional compounds. The assay was initially developed using a microarray platform. The authors then evaluated whether it could be transferred to a more cost-effective platform with higher throughput. The results indicate that a small set of genes can be used to quantitatively assess the degree to which a compound falls into a certain mechanistic toxicological class. While this study only focused on two classes, it could be expanded to encompass other toxicological mechanistic classes as well. Furthermore, by adapting this type of assay to a higher throughput platform, in vitro toxicogenomics can represent an effective approach to generate robust toxicological data early in the drug discovery process.

Animals↗
PubMed2006

HLA-B locus in Caucasian patients with carbamazepine hypersensitivity.

BACKGROUND: A strong pharmacogenetic association has been reported in Chinese patients between human leukocyte antigen (HLA)-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS). METHODS: We have genotyped the HLA-B alleles in 56 Caucasian patients with varying severities of CBZ hypersensitivity and 43 controls on CBZ without adverse effects. RESULTS: None of our patients (including two with blistering skin rashes) were positive for the HLA-B*1502 allele. HLA-B*0702 allele may protect against severe CBZ hypersensitivity but warrants further study. Of secondary interest, the correlation between HLA-B*0801 and HLA-DR3, DQ2 and TNF -308 alleles (on the ancestral haplotype 8.1) is consistent with our previous findings. CONCLUSION: HLA-B*1502 does not seem to be a marker for all forms of CBZ-induced hypersensitivity in a Caucasian population.

Alleles↗
PubMed2006

Relationships between genetic polymorphisms and anticancer drug cytotoxicity vis-à-vis the NCI-60 panel.

INTRODUCTION: The National Cancer Institute (NCI)-60 panel consists of 60 human tumor cell lines initially established for screening thousands of molecules for antiproliferative activity. It has been powerful for deciphering the relationships between anticancer drug cytotoxicity and cell molecular characteristics. We tested its potential interest for establishing relationships between the polymorphism of genes involved in drug metabolism and transport or in DNA repair, and drug cytotoxicity extracted from NCI databases. METHODS: Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques, three frequent single nucleotide polymorphisms (SNPs) were analyzed: Lys751Gln in the Xeroderma pigmentosum complementation group D (XPD, ERCC2) gene, Asp1104His in the Xeroderma pigmentosum complementation group G (XPG, ERCC5) gene and Ile105Val in the glutathione S-transferase P1 (GSTP1) gene. RESULTS: The allelic frequencies of the variants were 33% for ERCC2, 23% for ERCC5 and 39% for GSTP1. The ERCC2 polymorphism appeared to be a strong determinant of the in vitro cytotoxicity of most anticancer agents, with lower half maximal inhibitory concentration (IC50) values in variant homozygous lines than in common homozygous or heterozygous cell lines. Unexpectedly, the cytotoxicity of taxanes appeared markedly dependent upon the ERCC2 genotype, with threefold lower mean IC50 values in variant homozygous cell lines. The ERCC5 genotype appeared to be important only for taxanes, with fourfold higher IC50 values in variant homozygous cell lines. The GSTP1 polymorphism was related to the cytotoxicity of several drug classes, especially topoisomerase inhibitors, antimetabolites and N7 alkylating agents. CONCLUSION: The NCI-60 panel is capable of providing clues and tracks for the establishment of clinically useful relationships between a given genotype and the cytotoxicity of an anticancer agent.

Antineoplastic Agents↗
PubMed2006

Genetics of antipsychotic treatment emergent weight gain in schizophrenia.

Classic and modern antipsychotics can induce substantial weight gain causing diabetes, lipid abnormalities and psychological distress. Treatment emergent weight gain varies within the broad class of antipsychotics; however, an individual's propensity to develop weight gain largely depends on genetic factors. The first part of this review highlights current ideas and concepts related to antipsychotic-induced weight gain, including principles on energy homeostasis. The second part summarizes genetic findings emphasizing studies published after 2003 as prior studies have been reviewed in detail elsewhere. Candidate gene studies have produced significant findings in the 5-hydroxytryptamin 2C (5HT2C) and adrenergic alpha2a (ADRalpha2a) receptor genes, as well as in the leptin, guanine nucleotide binding protein (GNB3) and synaptomal-associated protein 25kDa (SNAP25) genes. Results from genome-wide association and linkage studies point to several chromosomal regions (e.g., 12q24) and some specific genes (e.g., promelanin concentrating hormone [PMCH], polycyctic kidney and hepatic disease 1 [PKHD1], peptidylglycine alpha-amidating monooxygenase [PAM]). However, more efforts are needed before risk prediction and personalized medicine can be made available for antipsychotic-induced weight gain.

Antipsychotic Agents↗
PubMed2006

Can pharmacogenetics help rescue drugs withdrawn from the market?

Observations over the later half of the last century have suggested that genetic factors may be the prime determinant of drug response, at least for some drugs. Retrospectively gathered data have provided further support to the notion that genotype-based prescribing will improve the overall efficacy rates and minimize adverse drug reactions (ADRs), making personalized medicine a reality. During the last 16 years, 38 drugs have been withdrawn from major markets due to safety concerns. Inevitably, a question arises as to whether it might be possible to 'rescue' some of these drugs by promoting genotype-based prescribing. However, ironically pharmacogenetics has not perceptibly improved the risk/benefit of a large number of genetically susceptible drugs that are already in wide clinical use and are associated with serious ADRs. Drug-induced hepatotoxicity and QT interval prolongation (with or without torsade de pointes) account for 24 (63%) of these 38 drug withdrawals. In terms of the number of drugs implicated, both these toxicities are on the increase. Many others have had to be withdrawn due to their inappropriate use. This paper discusses the criteria that a drug would need to fulfill, and summarizes the likely regulatory requirements, before its pharmacogenetic rescue can be considered to be realistic. One drug that fulfils these criteria is perhexiline (withdrawn worldwide in 1988) and is discussed in some detail. For the majority of these 38 drugs there are, at present, no candidates for genetic traits to which the toxicity that led to their withdrawal may be linked. For a few other drugs where a potential candidate for a genetic trait might explain the toxicity of concern, the majority of patients who experienced the index toxicity had easily managed nongenetic risk factors. It may be possible to rescue these drugs simply by careful attention to their dose, interaction potential and prescribing patterns, but without the need for any pharmacogenetic test. In addition, the pharmacogenetic rescue of drugs might not be as effective as anticipated as hardly any pharmacogenetic test is known to have the required test efficiency to promote individualized therapy. Multiple pathways of drug elimination, contribution to toxicity by metabolites as well as the parent drug, gene-gene interactions, multiple mechanisms of toxicity and inadequate characterization of phenotype account for this lack of highly predictive tests. The clinical use of tests that lack the required efficiency carries the risks of over- or under-dosing some patients, denying the drug to others and decreasing physician vigilance of patients. Above all, at present, prescribing physicians lack an adequate understanding of pharmacogenetics and its limitations. It is also questionable whether their prescribing will comply with the requirements for pretreatment pharmacogenetic tests to make pharmacogenetic rescue a realistic goal.

Adverse Drug Reaction Reporting Systems↗
PubMed2006

The genomics of new drugs in sickle cell disease.

The quality of life of patients with sickle cell disease in developed countries has improved significantly over the past two decades. Currently available measures to prevent the painful crises and the complications of the disease include the use of penicillin prophylaxis, antipneumonococcal vaccine, folate administration, chronic red cell transfusions in patients with cerebrovascular disease, iron chelating agents, fetal hemoglobin-enhancing agents, such as hydroxyurea, decitabine and butyrate, drugs that augment the endogenous nitric oxide levels and agents that restore red cell dehydration. Sickle cell patients show a broad phenotypic expression and a great variability in treatment response. Genetic association studies, which attempt to link polymorphisms with certain disease phenotypes and drug response, are taking the first steps in aiding individualized therapy in sickle cell patients in order to enhance efficacy and reduce toxicity.

Anemia, Sickle Cell↗
PubMed2006

Toxicogenomics strategies for predicting drug toxicity.

INTRODUCTION: The failure of pharmaceutical drug candidates due to toxicity, especially hepatotoxicity, is an important and continuing problem for drug development. The current manuscript explores new toxicogenomics approaches to better understand the hepatotoxic potential of human pharmaceutical compounds and to assess their toxicity earlier in the drug development process by means of a toxicity screen. RESOURCES: Data consisted of two commercial knowledgebases that employed a hybrid experimental design in which human drug toxicity information was extracted from the literature, dichotomized and merged with rat-based gene expression measures. One knowledgebase used gene expression from rat primary hepatocytes while the other employed whole rats. Approximately 100 compounds were used in each. METHODS: Toxicity classification rules were built using a stochastic gradient boosting machine learner, with classification error estimated using a modified bootstrap estimate of true error. Several types of clustering methods were also applied, some based on sets of compounds and others based on sets of genes. RESULTS: Robust classification rules were constructed for both in vitro (hepatocytes) and in vivo (liver) data, based on a high dose, 24-hour design. There appeared to be little overlap between the two classifiers, at least in terms of their gene lists. Robust classifiers could not be fitted when earlier timepoints and/or low dose data were included, indicating that experimental design is important for these systems. CONCLUSIONS: In light of these findings, a working compound screen based on these toxicity classifiers appears feasible, with classifier operating characteristics used to tune a screen for a specific implementation. To ensure robust and optimal performance, issues such as site variability of microarrays and generalizability of findings should be addressed as indicated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Toxicogenomics in drug discovery and development: mechanistic analysis of compound/class-dependent effects using the DrugMatrix database.

A range of genomics technologies are increasingly becoming integrated with existing scientific disciplines to broaden and strengthen existing capabilities and open new avenues of research in drug discovery and development. Examples of these new research fields are proteomics, pharmacogenomics, metabolomics and toxicogenomics. Here we review the application of toxicogenomics to improve the evaluation of drug safety, mechanism of action and toxicity in the drug discovery and development process.

Databases, Genetic↗
PubMed2004

Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia.

OBJECTIVE: To evaluate the haplotype distribution associated with the copper toxicosis gene and the segregation of the mutated allele in a Bedlington Terrier population in Australia. ANIMALS: 131 Bedlington Terriers. PROCEDURE: Samples of DNA and RNA were obtained from each dog. Genetic status of each dog was evaluated by use of the DNA markers C04107; single nucleotide polymorphism (SNP), which was adjacent to exon 2 of Murr1; and a deletion marker for exon 2. A subgroup of the study population was evaluated by use of biochemical and histologic techniques to elucidate the correlation between genotype and phenotype. RESULTS: We identified a recombination between the C04107 marker and Murr1 and a variation in a nucleotide in the splice site of exon 2 in our Bedlington Terrier cohort. Furthermore, we identified a novel haplotype associated with copper toxicosis in this cohort. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings indicate that the deletion of exon 2 was not the sole cause of copper toxicosis, although only exon 2 deletion of Murr1 has been responsible for copper toxicosis in Bedlington Terriers. Although we failed to find a novel mutation in our cohort, we identified an affected dog family with an intact exon 2. Furthermore, we found that an SNP in the 5' splicing site of exon 2 may or may not be associated with a novel mutation of the Murr1 gene or other genes. Loss of linkage between the C04107 marker and the Murr1 gene was also identified in a certain family of dogs.

Animals↗
PubMed2004

Trends in early drug safety.

Successful introduction of a new drug to the market is not only an extremely costly and complicated process, but also fraught with a substantial risk of failure. The number of new drugs launched each year from 1990 to 2000 has stayed relatively constant, while the cost of pharmaceutical research and development has risen by almost 2.5-fold over the same period. What is not revealed by these figures is that the chance of success for a drug candidate passing through the various hurdles in pharmaceutical development is at best 1 in 10 and has barely changed despite advancing technology in other areas of research and development. While we expect high failure rates in drug discovery, it is of substantial concern that most candidates in development on which large investments have already been made are probably not going to make any return. A major stumbling block is the absorption, distribution, metabolism, excretion and toxicology profile of drug candidates. These issues were discussed at the Society for Medicines Research symposium held September 18, 2003, in London, United Kingdom. Recent SMR symposia have focused on the ADME and pharmacokinetic aspects of drug discovery and development. Indeed, it is now uncommon for drug discovery projects not to address these issues early in their lifetimes. Although it is less common to address drug safety early in a project, it is being utilized more frequently to help select the best clinical candidates for further development. This meeting report summarizes some of the key aspects of early drug safety issues facing the drug discoverer today. Classical approaches to toxicology, p450-mediated safety, cardiovascular safety, "omics" approaches and their impact upon clinical safety will be discussed.

Animals↗
PubMed2004

[Toxicogenomics. New perspectives for the molecular toxicology].

Gene expression in the cellular genome is subject to changes caused by internal and external factors. Due to different expression of gene sets (polymorphism), cells show different morphological and functional characteristics. Environmental and occupational toxic agents may influence cells at the level of transcription and translation. The functional toxicogenomics attempts to explain those influences. Due to recent developments in molecular biology and bioinformatics, it has become possible to analyze protein transcript (toxicogenomics) and profile (toxicoproteomics). This work reports new opportunities to study gene sequencing and expression by means of the DNA chip technique (rapid analysis of the genetic polymorphism) and the microarrays technique (simultaneous analysis of hundreds or thousands of genes). The authors report examples of some practical applications of toxicogenomics in the assessment of the effects of pathological exposures to environmental and occupational toxic (carcinogenic, hepatotoxic and/or neurotoxic) agents, due to the development of new groups of biomarkers, such as biomarkers of individual susceptibility, biomarkers of toxic effects combined with the assay of the relationship between a toxic agent and its dose, and the effect measured at the level of the cellular genome and results of histopathological and biochemical tests.

Carcinogens, Environmental↗