Science and Technology

Listen to Paula Lapinskas, Ph.D. Molecular Toxicology as she describes using Metabolomics to profile effects of Rapamycin on metabolic pathways in human primary adipocytes and hepatocytes. This presentation is based on work performed at Signal Pharmaceuticals, LLC (a wholly-owned subsidiary of Celgene Corp.). Analysis includes a discussion about the use of global biochemical profiling and its application in drug action and toxicology.

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Application Focus

Metabolomic Analysis of Urine and Kidney Tissue in Rats Treated with Valproate

Moti Rosenstock; Teva Pharmaceutical Industries Ltd., Non-Clinical Development Department, Teva Innovative Ventures, P.O. Box 8077, Netanya 42504, Israel;
Kurt Boudonck; Metabolon Inc., 800 Capitola Drive, Suite 1, Durham, NC 27713, U.S.A.

Summary: Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. In order to better understand its mechanism of action and toxicity profile, a globally unbiased metabolomic analysis was performed. Sprague-Dawley Crl:CD(SD) rats were treated with VPA (500 mg/kg) or saline (vehicle) once daily for 1, 5 or 28 days. Urine and kidney tissue samples were collected from groups of 6 rats each (12 rats for vehicle group) at days 1, 5 and 28. Full data curation of kidney tissue samples yielded 547 metabolites, and urine yielded 657 metabolites, consisting of amino acid metabolites, peptides, carbohydrates, lipids, energy metabolites, nucleotides, cofactors, vitamins and xenobiotics. Over 130 metabolites were found to be significantly different in urine between vehicle and VPA-treated groups at each time point. Request This Poster

Global Biochemical Analysis for Cell Line Selection and Media Development

Kirk Beebe, Ph.D., Michael Milburn, Ph.D. and Jeffrey Pfohl, M.S.
Metabolon, Inc., 800 Capitola Drive, Suite 1, Durham, NC 27713 USA

Summary: Maximizing production of biologicals from cultures is a stepped process often requiring multiple rounds of cause and effect experiments with analysis of production and quality as the end point drivers. From selection of clonal isolates to initial media formulations to scale up conditions there are many areas of experimentation which can be utilized for optimization of production. Request This Poster

Metabolite Biomarkers of Prostate Cancer

D. Alexander, K-P. Adam, A. Berger, C. Chirilla, M. Mitchell, J. R. Shuster

Metabolon, Inc., 800 Capitola Drive, Suite 1, Durham, NC 27713;

R. J. Lonigro, L. M. Poisson, Y. Li, J. Siddiqui, J. T. Wei, A. M. Chinnaiyan, A. Sreekumar

University of Michigan Medical School, Ann Arbor, MI 48109.

Summary: By all diagnostics methods in use today, it is difficult to determine with surety which prostate cancers are indolent, and which are aggressive and have the potential to metastasize. This is particularly true for prostate cancers identified as Gleason grades 6 7. Diagnostic tests that distinguish indolent from aggressive tumors have the potential to reduce the number of unnecessary biopsies and prostatectomies. Prostate cancer (PCa) aggressivity was investigated at the biochemical level in an unbiased fashion by using LC/MS and GC/MS based metabolomics to study differences between benign (adjacent) prostate tissue, and localized and metastatic PCa. Statistical analysis of the metabolomics data was performed using Random Forest analysis, two-way t-tests, and disproportionate representation analysis. The results indicated that 15% of the compounds analyzed were significantly changed (p<0.05) between benign and localized PCa, 52% changed between localized and metastatic cancer, and 61% changed between benign and metastatic cancer. In addition to the tissue work, similar unbiased metabolomics analysis was performed on independent urine samples obtained from post digital rectal exam patients who were at-risk for PCa. All of these patients underwent a biopsy procedure and the metabolomics data was compared with the results of the biopsy test. Interestingly, a subset of compounds that correlated with PCa aggressivity were observed in both the tissue and urine studies. One identified compound, methylglycine, is of particular interest since it has a role in buffering methyl groups that are known to be correlated with prostate cancer progression. Request This Poster

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