When Good Drugs Go Bad
Posted March 13, 2010
The first meeting of the Academy's Predictive Toxicology Discussion Group, held on November 14, 2005, discussed the search for biomarkers of toxicity, molecules that appear, disappear, or change in quantity when toxic effects are occurring.
Wayne Rosenkrans provided an overview of how biomarkers could be used, not just to predict drug toxicity, but also to allow physicians to monitor and treat diseases with much greater precision than they do now. Michael Lawton described the problem of drug-induced vascular injury, which is a common response of rats to preclinical toxicology tests, but has no direct parallel in humans and thus can confound drug safety studies. Donna Mendrick spoke about her studies of drug-induced kidney injury, which utilize the gene expression databases her company has prepared for use in what are now called toxicogenomic studies. And Alexandra Heinloth described her efforts to validate the genomic approach to toxicology by applying it to the well studied but still poorly understood problem of acetaminophen toxicity.
Use the tabs above to view the meeting report and multimedia presentations.
Drug-induced Vascular Injury—A Search for Biomarkers
White paper by an expert working group for the Nonclinical Studies subcommittee of the Advisory Committee on Pharmaceutical Science of the FDA in September 2002. Michael Lawton is a contributor.
Genomics at FDA
Report on the FDA's efforts to standardize genetic tests and disseminate information about them to health care providers and consumers.
Health and Human Services Secretary's Advisory Committee report on Genetics, Health, and Society
A public forum for deliberations on human health and societal issues raised by the use of genetic technologies.
Personalized Medicine Coalition
A nongovernmental, nonprofit group established to advance the understanding and adoption of personalized medicine. Includes biotechnology and pharmaceutical companies as well as federal agencies like the National Cancer Institute.
The National Institute of Environmental Health Sciences
Includes the National Toxicology Program and the National Center for Toxicogenomics.
The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB)
An integrated knowledge base for pharmacogenetics linking genetic data and clinical information.
The Pharmacogenetics Research Network (PGRN)
The Pharmacogenetics Research Network (PGRN) is a nationwide collaboration of scientists studying the effect of genes on people's responses to a wide variety of medicines.
The Society of Toxicologic Pathology (STP)
A nonprofit association of pathologists and other scientists whose principal aim is the advancement of pathological changes caused by pharmacological, chemical and environmental agents.
The Impact of Personalized Medicine
Collins, F. S., E. D. Green, A. E. Guttmacher, et al. 2003. A vision for the future of genomics research. Nature 422: 835-847.
Fierz, W. 2004. Challenge of personalized health care: to what extent is medicine already individualized and what are the future trends? Med. Sci. Monit. 10: RA111-123. (PDF, 475 KB) Full Text
Frueh, F. W & D. Gurwitz. 2004. From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5(5): 571-579.
Hapgood, R. 2003. The potential and limitations of personalized medicine in the doctor-patient relationship. Pharmacogenomics 4: 685-687.
Jain, K. K. 2004. Role of pharmacoproteomics in the development of personalized medicine. Pharmacogenomics 5: 331-336.
Langheier, J. M. & R. Snyderman. 2004. Prospective medicine: the role for genomics in personalized health planning. Pharmacogenomics 5: 1-8.
Molidor, R, A. Sturn, M. Maurer, et al. 2003. New trends in bioinformatics: from genome sequence to personalized medicine. Exp. Gerontol. 38: 1031-1036.
Nevins, J. R., E. S. Huang, H. Dressman, et al. 2003. Towards integrated clinico-genomic models for personalized medicine: combining gene expression signatures and clinical factors in breast cancer outcomes prediction. Hum. Mol. Genet. Spec. No. 2: R153-157. Full Text
Sullivan, C. G. 2004. How personalized medicine is changing the rules of drug life exclusivity. Pharmacogenomics 5: 429-432.
Weston, A.D. & L. Hood. 2004. Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J. Proteome Res. 3:179-196.
Measuring Gene Expression in Blood Vessels: The Challenges of Applying Toxicogenomics to Drug-induced Vascular Injury
Brott, D., S. Gould, H. Jones, et al. 2005. Biomarkers of drug-induced vascular injury. Toxicol. Appl. Pharmacol. 207: 441-445.
Cuellar, M. L. 2002. Drug-induced vasculitis. Curr. Rheumatol. Rep. 4: 55-59.
Doyle, M. K. & M. L. Cuellar. 2003. Drug-induced vasculitis. Expert Opin. Drug Saf. 2: 401-409.
Kerns, W, L. Schwartz, K. Blanchard, et al. 2005. Drug-induced vascular injury—a quest for biomarkers. Toxicol. Appl. Pharmacol. 203: 62-87.
Schwarz, M. I. & A.P. Fontenot. 2004. Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin. Chest Med. 25: 133-140.
ten Holder, S. M., M. S. Joy & R. J. Falk. 2002. Cutaneous and systemic manifestations of drug-induced vasculitis. Ann. Pharmacother. 36: 130-147.
Pharmacogenomic Biomarker Discovery
Cai, J., A. Cheng, Y. Luo, et al. 2004. Membrane properties of rat embryonic multipotent neural stem cells. J. Neurochem. 88: 212-226.
Castle, A. L., M. P. Carver & D. L. Mendrick. 2002. Toxicogenomics: a new revolution in drug safety. Drug Discov. Today 7: 728-736.
Davis, J. W. 2nd, F. M. Goodsaid, C. M. Bral, et al. 2004. Quantitative gene expression analysis in a nonhuman primate model of antibiotic-induced nephrotoxicity. Toxicol. Appl. Pharmacol. 200: 16-26.
Gibbs, A. 2005. Comparison of the specificity and sensitivity of traditional methods for assessment of nephrotoxicity in the rat with metabonomic and proteomic methodologies. J. Appl. Toxicol. 25: 277-295.
Muramatsu, Y., M. Tsujie, Y. Kohda, et al. 2002. Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int. 62: 1601-1610.
Sawai, K., K. Mori, M. Mukoyama, et al. 2003. Angiogenic protein Cyr61 is expressed by podocytes in anti-Thy-1 glomerulonephritis. J. Am. Soc. Nephrol. 14: 1154-1163. (PDF, 628 KB) Full Text
Yaghoobi, M. M., S. J. Mowla & T. Tiraihi. 2005. Nucleostemin, a coordinator of self-renewal, is expressed in rat marrow stromal cells and turns off after induction of neural differentiation. Neurosci. Lett. 390: 81-86.
Genomic Detection of Incipient Acetaminophen Toxicity in BloodBlackburn, A. C., K. I. Matthaei, C. E. Lim, et al. 2005. Deficiency of glutathione transferase Zeta causes oxidative stress and activation of antioxidant response pathways. Mol. Pharmacol. (PDF, 785 KB) Full Text
Chan, V.S. & M. D. Theilade. 2005. The use of toxicogenomic data in risk assessment: a regulatory perspective. Clin. Toxicol (Phila). 43: 121-126.
Heinloth, A.N., R. D. Irwin, G. A. Boorman, et al. 2004. Gene expression profiling of rat livers reveals indicators of potential adverse effects. Toxicol. Sci. 80: 193-202. (PDF, 881 KB) Full Text
Hinson, J. A, A. B. Reid, S. S. McCullough, et al. 2004. Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab. Rev. 36: 805-822.
Irwin, R. D., G. A. Boorman, M. L. Cunningham, et al. 2004. Application of toxicogenomics to toxicology: basic concepts in the analysis of microarray data. Toxicol. Pathol. 32: 72-83.
James, L. P., P. R. Mayeux & J. A. Hinson. 2003. Acetaminophen-induced hepatotoxicity. Drug Metab. Dispos. 31: 1499-1506. Full Text
Koop, R. 2005. Combinatorial biomarkers: From early toxicology assays to patient population profiling. Drug Discov. Today. 10: 781-788.
Peters, T. S. 2005. Do preclinical testing strategies help predict human hepatotoxic potentials? Toxicol. Pathol. 33: 146-154.
Tolson, J. K., D. J. Dix, R. W. Voellmy, et al. 2006. Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice. Toxicol. Appl. Pharmacol. 210: 157-162.
Wayne A. Rosenkrans, PhD
e-mail | publications
Wayne Rosenkrans is Business Strategy Director for External Scientific Affairs at AstraZeneca Pharmaceuticals, and serves as Strategy Co-chair of the Personalized Medicine Coalition.
Rosenkrans is a recipient of the Society of Competitive Intelligence Professionals (SCIP) Fellows Award, and a former president of the Society. Previous positions include Global Director, Intelligence Affairs at AstraZeneca, Director of U.S. Intelligence at AstraZeneca, Competitive Technical Intelligence Group Leader and Research Planning Analyst at Zeneca Pharmaceuticals, Director of Strategic Intelligence Systems for Windhover Information, Director of Drug Intelligence Systems Sales and Marketing for Adis International, and Associate Director and Head of Strategic Intelligence for SmithKline Beecham Pharmaceuticals R&D. He has presented at various forums on aspects of strategy development, strategic early warning, and strategic intelligence.
Rosenkrans holds an SB in biology from MIT and a PhD in cell and molecular biology from Boston University, and received postdoctoral training in cancer and radiation biology at the University of Rochester.
Michael P. Lawton, PhD
e-mail | publications
Michael Lawton heads the toxicogenomics laboratory and provides scientific guidance to the toxicoinformatics and bioanalytical technologies laboratories at Pfizer Inc. in Groton, Connecticut, where he has been employed since 1994. Before joined Pfizer, he performed postdoctoral work at the National Institute of Environmental Health Sciences. Lawton received a PhD in toxicology from North Carolina State University in 1991, where his thesis work concerned the molecular biology of mammalian flavin-containing monooxygenases.
Donna L. Mendrick, PhD
e-mail | publications
Donna Mendrick joined Gene Logic, located in Gaithersburg, Maryland, in 1998 to spearhead its toxicogenomics effort. She also serves as a member of the steering committee for the FDA cosponsored workshops on the use of genomic data in the regulatory environment. Prior to joining Gene Logic, Mendrick was a group leader in pharmacology at Human Genome Sciences Inc., where she directed several project teams. Before moving to industry, she was an assistant professor in the pathology department at Harvard Medical School, where her research focused on renal immunopathology and endothelial biology.
Alexandra N. Heinloth, MD
National Institute for Environmental and Health Sciences
e-mail | web site | publications
Alexandra Heinloth is a senior research fellow in the microarray group headed by Richard S. Paules at the National Institute for Environmental and Health Sciences (NIEHS), located at Research Triangle Park in North Carolina. She designs and coordinates genomic and in vivo studies of hepatotoxic agents. Before coming to NIEHS in 2000, she studied the effects of atherogenic lipoproteins on apoptosis of human macrophages under Bernhard Brüne of the University of Erlangen. She holds a medical degree from the University of Würzburg, Germany.
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.