Disease Markers - Volume 18, issue 2

Authors: Srivastava, Sudhir | Wagner, John A.

Article Type: Other

Citation: Disease Markers, vol. 18, no. 2, pp. 39-40, 2002

Authors: Wagner, John A.

Article Type: Research Article

Abstract: There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful …biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker for {\it in vivo} activation of peroxisome proliferator-activated receptors (PPAR) γactivity. Show more

Keywords: Acrp30, adiponectin, biomarkers, clinical endpoint, pharmacodynamic marker, PPARγ, surrogate endpoint, type 2 diabetes

Citation: Disease Markers, vol. 18, no. 2, pp. 41-46, 2002

Authors: Swanson, Brian N.

Article Type: Research Article

Abstract: Biomarker measurements now support key decisions throughout the drug development process, from lead optimization to regulatory approvals. They are essential for documenting exposure-response relationships, specificity and potency toward the molecular target, untoward effects, and therapeutic applications. In a broader sense, biomarkers constitute the basis of clinical pathology and laboratory medicine. The utility of biomarkers is limited by their specificity and sensitivity toward the drug or disease process and by their overall variability. …Understanding and controlling sources of variability is not only imperative for delivering high-quality assay results, but ultimately for controlling the size and expense of research studies. Variability in biomarker measurements is affected by: biological and environmental factors (e.g., gender, age, posture, diet and biorhythms), sample collection factors (e.g., preservatives, transport and storage conditions, and collection technique), and analytical factors (e.g., purity of reference material, pipetting precision, and antibody specificity). The quality standards for biomarker assays used in support of nonclinical safety studies fall under GLP (FDA) regulations, whereas, those assays used to support human diagnostics and healthcare are established by CLIA (CMS) regulations and accrediting organizations such as the College of American Pathologists. While most research applications of biomarkers are not regulated, biomarker laboratories in all settings are adopting similar laboratory practices in order to deliver high-quality data. Because of the escalation in demand for biomarker measurements, the highly-parallel (multi-plexed) assay platforms that have fueled the rise of genomics will likely evolve into the analytical engines that drive the biomarker laboratories of tomorrow. Show more

Keywords: assay, bioanalytical, biomarker, CLIA, drug development, GLP, pharmaceutical, quality, regulations, review, validation

Citation: Disease Markers, vol. 18, no. 2, pp. 47-56, 2002

Authors: Sides, Gregory D.

Article Type: Research Article

Abstract: Prolongation of the QT interval on the surface 12-lead electrocardiogram is widely accepted as a biomarker for the potential of a drug to produce torsades de pointes and/or sudden death. Detection of drug-induced prolongation of the QT interval in animals and man is frequently confounded by extrinsic and intrinsic factors that limit the ability to detect a true drug effect. In particular drugs that increase heart rate show an apparent increase in QT interval that confounds …assessment of a true drug effect on cardiac ventricular repolarization. The basis for the use of the QT interval as a biomarker will be examined. Show more

Citation: Disease Markers, vol. 18, no. 2, pp. 57-62, 2002

Authors: Kirkwood, Sandra C. | Hockett, Jr., Richard D.

Article Type: Research Article

Abstract: Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that …stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity. Prior to the widespread clinical application of a genetic biomarker multiple scientific studies must be completed to identify the genetic variants and delineate their functional significance in the pathophysiology of a carefully defined phenotype. The applicability of the genetic biomarker in the human population must then be verified through both retrospective studies utilizing stored or clinical trial samples, and through clinical trials prospectively stratifying patients based on the biomarker. The risk conferred by the polymorphism and the applicability in the general population must be clearly understood. Thus, the development and widespread application of a pharmacogenomic biomarker is an involved process and for most disease states we are just at the beginning of the journey towards individualized therapy and improved clinical outcome. Show more

Keywords: pharmacogenomics, biomarkers

Citation: Disease Markers, vol. 18, no. 2, pp. 63-71, 2002

Authors: Kiviat, Nancy B. | Critchlow, Cathy W.

Article Type: Research Article

Abstract: Implementation of routine cancer screening accompanied by treatment of early stage disease is paramount to realizing reductions in cancer mortality rates. While morphologic assessment of relevant cells has traditionally been used to identify individuals with cancer, this approach is not feasible to identify cancers at inaccessible sites, such as the ovary or pancreas. For these and many other cancers, cancer mortality remains high, as sensitive and specific screening assays to detect in-situ or early stage disease …are as yet unavailable. Identification of novel markers for early identification of cancer is an established priority of the National Cancer Institute. The rapid expansion of genomic-based technologies developed over the last decade, and the development of sensitive and specific blood-based assays for the detection of molecular changes associated with cancer, begin to offer the means for achieving this goal. Below, we review current approaches used in the effort to identify biomarkers appropriate for early cancer detection. Show more

Keywords: cancer biomarkers, genomic-based screening, early cancer detection

Citation: Disease Markers, vol. 18, no. 2, pp. 73-81, 2002

Authors: Lathia, Chetan D.

Article Type: Research Article

Abstract: As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs is described in this review. …Additionally, the utility of pharmacokinetic data in drug development is described. Development of biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process. Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by clinicians to evaluate the potential for efficacy after start of treatment. Show more

Citation: Disease Markers, vol. 18, no. 2, pp. 83-90, 2002

Authors: Kantor, Aaron B.

Article Type: Research Article

Abstract: There is an enormous unmet need for biological markers to characterize disease type, status, progression, and response to therapy. We are developing and applying an integrated bioanalytical platform and clinical research program to facilitate comprehensive differential phenotyping of patient samples and enable the discovery of biomarkers. The platform employs high-throughput, quantitative analysis for the characterization of thousands of parameters including cell populations, cell-surface antigen density, soluble proteins and soluble low molecular weight …biomolecules, from small-volume biological samples in a clinical research laboratory-like setting. Show more

Keywords: biomarker, cytometry, proteomics, mass spectrometry, clinical studies

Citation: Disease Markers, vol. 18, no. 2, pp. 91-97, 2002

Authors: McDonald, W. Hayes | Yates III, John R.

Article Type: Research Article

Abstract: Coupling large-scale sequencing projects with the amino acid sequence information that can be gleaned from tandem mass spectrometry (MS/MS) has made it much easier to analyze complex mixtures of proteins. The limits of this "shotgun" approach, in which the protein mixture is proteolytically digested before separation, can be further expanded by separating the resulting mixture of peptides prior to MS/MS analysis. Both single dimensional high pressure liquid chromatography (LC) and multidimensional LC (LC/LC) can be …directly interfaced with the mass spectrometer to allow for automated collection of tremendous quantities of data. While there is no single technique that addresses all proteomic challenges, the shotgun approaches, especially LC/LC-MS/MS-based techniques such as MudPIT (multidimensional protein identification technology), show advantages over gel-based techniques in speed, sensitivity, scope of analysis, and dynamic range. Advances in the ability to quantitate differences between samples and to detect for an array of post-translational modifications allow for the discovery of classes of protein biomarkers that were previously unassailable. Show more

Keywords: proteomics, proteome, biomarker, MudPIT, mass spectrometry, multidimensional chromatography

Citation: Disease Markers, vol. 18, no. 2, pp. 99-105, 2002