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Biomedical subjects

James W Watters

Publications and source records attributed to James W Watters.

14 recordsLinked to original sources
PubMed2006

Developing gene expression signatures of pathway deregulation in tumors.

Recent advances in our understanding of cancer biology have led to the development of therapies targeting specific signaling pathways. Molecular targeting promises to improve our ability to predict who will respond by assessing the state of these targeted pathways in patients. However, a single pathway can be deregulated by multiple mechanisms, and for some pathways it may be difficult to assess activation state by analyzing a single oncogene or tumor suppressor. Therefore, developing gene expression signatures of pathway activation status using model systems or human tumor samples may enable a more reliable measurement of pathway activity. This review discusses recent advances in the identification of gene expression-based signatures of pathway deregulation and how this information may lead to improved therapeutic response prediction.

Animals↗
PubMed2005

CEPH individuals are representative of the European American population: implications for pharmacogenetics.

Previous studies have highlighted the use of phenotype generation in immortalized lymphoblastoid cells from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees as a powerful means of discovering genes involved in complex biological and pharmacological phenotypes. However, there is no data on how representative CEPH pedigrees are of the general population of European origin for genetic variants of pharmacogenetic significance. A vast amount of data in a population of restricted applicability would be of little value. Genotype and allele frequencies of 28 variants in 15 pharmacogenetically relevant genes were analyzed in germ-line DNA from European- and African-origin blood donors, and CEPH cell lines of European origin. The results demonstrate that allele frequencies for the 28 polymorphisms are highly similar between the CEPH and the European-origin populations. However, genotype frequencies in the CEPH population did not provide a high level of prediction for the African-origin population. These data support the usefulness of the CEPH panel in pharmacogenetic discovery efforts for European-derived populations.

Black People↗
PubMed2004

Genome-wide discovery of loci influencing chemotherapy cytotoxicity.

Little is known about the heritability of chemotherapy activity or the identity of genes that may enable the individualization of cancer chemotherapy. Although numerous genes are likely to influence chemotherapy response, current candidate gene-based pharmacogenetics approaches require a priori knowledge and the selection of a small number of candidate genes for hypothesis testing. In this study, an ex vivo familial genetics strategy using lymphoblastoid cells derived from Centre d'Etude du Polymorphisme Humain reference pedigrees was used to discover genetic determinants of chemotherapy cytotoxicity. Cytotoxicity to the mechanistically distinct chemotherapy agents 5-fluorouracil and docetaxel were shown to be heritable traits, with heritability values ranging from 0.26 to 0.65 for 5-fluorouracil and 0.21 to 0.70 for docetaxel, varying with dose. Genome-wide linkage analysis was also used to map a quantitative trait locus influencing the cellular effects of 5-fluorouracil to chromosome 9q13-q22 [logarithm of odds (LOD) = 3.44], and two quantitative trait loci influencing the cellular effects of docetaxel to chromosomes 5q11-21 (LOD = 2.21) and 9q13-q22 (LOD = 2.73). Finally, 5-fluorouracil and docetaxel were shown to cause apoptotic cell death involving caspase-3 cleavage in Centre d'Etude du Polymorphisme Humain lymphoblastoid cells. This study identifies genomic regions likely to harbor genes important for chemotherapy cytotoxicity using genome-wide linkage analysis in human pedigrees and provides a widely applicable strategy for pharmacogenomic discovery without the requirement for a priori candidate gene selection.

Antineoplastic Agents↗
PubMed2004

Simple and rapid docetaxel assay in plasma by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry.

A simple, rapid and low cost sample preparation method was developed for quantification of docetaxel in mouse plasma by high-performance liquid chromatography/tandem mass spectrometry with paclitaxel as the internal standard. A small volume of plasma (40 microl) and one-step protein precipitation using methanol and acetonitrile (1:1 (v/v)) were used for sample preparation. The calibration curve for docetaxel in mouse plasma was linear over the range 25-2500 nM. The detection limit was 8 nM. The lower limit of quantitation is 25 nM. The intra- and inter-day precisions (CV) of analysis were 9.5 and 9.7% for the low quality control (LQC), 5.5 and 4.9% for the medium quality control (MQC) and 3.9 and 6.3% for the high quality control (HQC), respectively. The accuracy was 102.5% for LQC, 97.9% for MQC and 108.8% for HQC. This assay has now been applied to evaluation of mouse pharmacogenetics and other clinical pharmacology applications.

Animals↗
PubMed2004

Analysis of variation in mouse TPMT genotype, expression and activity.

Although the mouse has great potential for pharmacogenomic discovery, little is known about variation in drug response or genetic variation in pharmacologically relevant genes between inbred mouse strains. We therefore assessed variation in gene sequence, mRNA expression and protein activity of thiopurine methyltransferase (TPMT) in multiple inbred mouse strains. TPMT activity was measured by high-performance liquid chromatography detection of 6-MMP produced by incubation of liver homogenates with 6-MP. Genetic variation was assessed by resequencing and single nucleotide polymorphism (SNP) genotyping using pyrosequencing technology. mRNA expression was measured by real-time polymerase chain reaction. We observed an almost five-fold variation in TPMT activity, with strains falling into distinct low and high activity groups. This pattern of TPMT activity was highly correlated with expression of TPMT mRNA among strains, and high TPMT expression is dominant in F1 hybrids. To correlate genotype with phenotype, 29 SNPs and one insertion/deletion were genotyped throughout the TPMT gene and upstream 10 kb. Only two haplotypes were observed across all 30 polymorphisms, corresponding to the low and high activity groups. These results suggest that differential mouse TPMT activity is due to variation in mRNA expression. In addition, the identified pattern of low haplotype diversity suggests that the mouse is likely to be useful for pharmacogenomic discovery by associating haplotype blocks with drug response phenotypes among inbred strains.

Amino Acid Sequence↗
PubMed2004

Pharmacogenomics: the influence of genomic variation on drug response.

Unpredictable efficacy and toxicity are major hurdles in the administration of many medications. By identifying inherited DNA polymorphisms that influence drug disposition and effects, pharmacogenomics is an exciting tool for the individualization of drug therapies. Single nucleotide polymorphisms (SNP) in genes encoding drug metabolizing enzymes, drug transporters, and DNA repair genes have recently been shown to influence drug toxicity and efficacy. This review will discuss clinically relevant examples of genetic polymorphisms that influence the outcome of drug therapy, and possibilities for future applications of pharmacogenomics.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Cancer pharmacogenomics: current and future applications.

Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug metabolizing enzymes and other molecules are responsible for much of the interindividual differences in the efficacy and toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence the outcome of cancer therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting cancer pharmacogenomics. The power and utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of cancer therapy.

Animals↗
PubMed2003

Using genome-wide mapping in the mouse to identify genes that influence drug response.

Differential drug response is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. As a result of theoretical and technical limitations, to date, most clinically useful pharmacogenomic studies in humans have been limited to a small number of candidate genes that have a relatively major impact on drug response. Here, the problems involved in identifying genes that underlie drug response in humans are discussed and the power of mouse genetics as a tool for pharmacogenomic discovery is highlighted.

Animals↗
PubMed2003

A mouse-based strategy for cyclophosphamide pharmacogenomic discovery.

Genome-wide mapping approaches are needed to more fully understand the genetic basis of chemotherapy response. Because of technical and ethical limitations, cancer pharmacogenomics has not yet benefited from traditional robust familial genetic strategies. We have therefore explored the use of the inbred mouse as a genetic model system in which to study response to the cytotoxic agent cyclophosphamide. Multiple phenotypes have been assessed in response to cyclophosphamide in up to 19 inbred mouse strains, including in vitro hematopoietic progenitor cell toxicity and the mobilization of hematopoietic progenitor cells into peripheral blood. Hematopoietic progenitor cell toxicity in vitro varied 2-fold among strains, whereas in vivo progenitor cell mobilization varied almost 75-fold among strains. Males mobilized more hematopoietic progenitor cells than did females, and the low-mobilization phenotype was dominant to the high-mobilization phenotype in F1 hybrid animals. In an initial attempt to analyze candidate genes, genetic variation was assessed in three cytochrome P-450 genes involved in the metabolism of cyclophosphamide. Resequencing of eight strains identified 26 polymorphisms in these genes that may influence response to cyclophosphamide. Distinct regions of high- and low-polymorphism rates were identified, and two common haplotypes were shared among the strains for each gene that exhibited variation. This phenotypic and genotypic variation among inbred strains provides a framework for cyclophosphamide pharmacogenomic discovery.

Animals↗
PubMed2003

Using genetic variation to optimize cancer chemotherapy.

The high level of interpatient variation in response to chemotherapy and the lack of objective tools to select chemotherapy regimens for a given tumor type have created a clinical problem. A possible solution may be pharmacogenetics: the study of inherited DNA polymorphisms that influence drug disposition and effects in order to individualize drug treatment. Because unpredictable efficacy and high levels of systemic toxicity are common in cancer chemotherapy, pharmacogenetics is particularly appealing to oncologists. Polymorphisms in drug metabolism, drug transport, drug target, and DNA repair genes have been implicated interpatient variability in response to many chemotherapy agents. This review will discuss recent clinically relevant examples of cancer pharmacogenetics and how genetic differences are helping to shape the future of individualized cancer chemotherapy.

Antineoplastic Agents↗
PubMed2002

Murine pharmacogenomics: using the mouse to understand the genetics of drug therapy.

Pharmacogenomics seeks to understand the genetic basis of interindividual differences in drug disposition and effects. Differential drug response is likely to most often be a complex trait, in which multiple genes contribute with varying strengths to the therapeutic phenotype. Due to technical and economic limitations, pharmacogenomic studies in humans are mainly limited to a small number of candidate genes with relatively major influences on drug response. This review discusses the problems involved in mapping genes underlying drug response in humans and highlights the theoretical and applied uses of mouse genetics to address these important issues.

Animals↗
PubMed2002

Recent advances in the pharmacogenetics of cancer chemotherapy.

Patient response to chemotherapy varies widely between individuals. Pharmacogenetics is the study of inherited DNA polymorphisms that influence drug disposition and effects, the goal of which is the individualization of drug treatment. As unpredictable efficacy and high levels of systemic toxicity are common in cancer chemotherapy, pharmacogenetics is particularly appealing for oncology. Recent studies have shown that polymorphisms in genes involved in drug metabolism, nucleotide synthesis and DNA repair contribute to inter-patient variability in the efficacy and toxicity of many chemotherapy agents. This review will discuss recent developments in the most clinically relevant examples of cancer pharmacogenetics, and how genetic differences among individuals are shaping the future of cancer chemotherapy.

Animals↗