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Advanced In Vitro Toxicology Program

New technologies are generating more drug candidate leads, yet developers face challenges. Of drugs in development, one in 10-12 succeeds in clinical use. In the last 20 years drug development costs have risen sixfold (to between $500 and 800 million per approved drug), stimulating pressure to reduce costs. Time to market can take more than 11 years, resulting in a shortened patent life and lower return on investment.

Improving R&D efficiencies by reducing failure rates would lower costs significantly.  More effective testing paradigms are needed to accomplish this. Reliable in vitro target organ systems can help identify the most promising leads by more accurately predicting human toxicity and therapeutic indices before drugs enter the clinic.

SRI's Advances

SRI is developing improved or novel mammalian multicellular systems to meet this need. These improved systems can be used to answer toxicological questions and provide semiquantitative and quantitative information on organ effects not otherwise available.

Our strategy is to model in vivo systemic effects using multicellular systems that contain the target and modulator cells involved in toxicity mechanisms. We have tested the hypotheses that animal and human precision-cut slices can meet those criteria using liver and lung slices. Using traditional clinical chemistry metrics, immunohistochemistry, and histology, we demonstrated that hepatobiliary and pulmonary toxicants induce recognizable lesions and biochemical changes consistent with their known effects in vivo. We were able to optimize the methods for high quality long-term slice cultures to detect and study delayed and "chronic", as well as acute effects.

Ultimately, SRI intends to perfect and integrate a test battery of model systems for accurate prediction of human toxic potency and dose-limited toxicities during preclinical toxicology testing of drug candidates.

Our advances include the following:

Liver:

• Improved method of preparation and culture
• Long-term culture (rat: 21 days, dog: 7 days, human in progress)
• Biliary lesions (necrosis, cell proliferation, fatty liver, stasis)
• Integrated clinical chemistry response/histology
• Ranking hepatobiliary toxicants
  

For more information:

• 2003 SOT meeting poster (PDF)
  H. P. Behrsing, A. E. Vickers, and C. A. Tyson (2003). Extended rat liver slice survival and stability monitored using clinical biomarkers. Biochem Biophys Res Commun 312(1): 209-13.
  
• 2004 Tissue Models for Drug Discovery poster (PDF)

Lung:

• Improved method of purification and culture
• Long-term culture (rat and dog: 28 days, human in progress)
• Lesions (interstitial pneumonitis, fibrosis, dysplasia)
• Ranking pulmonary toxicants

For more information:

• 2004 SOT meeting poster (PDF)
  
• 2004 Tissue Models for Drug Discovery poster (PDF)

• Prediction of what kinds of lesion to expect in vivo
• Ranking relative toxic potency of compounds/analogues more accurately
  
• Prediction of species susceptibility and dose-limiting toxicities
• Establishment of early marker relationships with lesion development (genomics/proteomics)
• Detection and investigation of longer-term effects (delayed toxicity, "chronic" lesions)
• Prediction of clinical chemistry patterns to expect in vivo vs. time/exposure
• Provision of scale-up data for preliminary assessment of safe exposure levels
• Picking up effects not possible with single cell systems alone (i.e. hepatocytes, alveolar macrophages); more like in vivo

• "Prediction of long-term toxicity of NCEs in key organs is of utmost importance. In vitro models for such applications have not been validated." Report ECVAM Workshop 45, ATLA 2003.
• "Exciting preliminary evidence that lung rat slice model can be extended to 28 days in culture. This breakthrough creates a new opportunity to study pulmonary diseases that arise from chronic exposure to medications." Summary Statement, R33 grant from NCI, April 2004.
• "Assays that predict the correct biomarker/histological changes drugs make and in vivo MTDs in humans at physiologically relevant exposures are exactly what we need. Bone marrow, liver, and lung assays are among the most important for anticancer therapeutics." NIH Roadmap ADMET Workshop, Bethesda, June 2004.

Team Expertise

Khalid Amin, M.D.
Biochemist/Histopathologist
khalid.amin@sri.com

Dr. Amin received his M.D. from Rawalpindi Medical College, and completed his fellowship training in histopathology from the Armed Forces Institute of Pathology in Pakistan. He received his postdoctoral training in experimental pathology at Duke University Medical Center, Durham, NC. Dr. Amin provides the histological analysis of slice tissue and directs the selection of biomarkers for immunohistochemical staining. His extensive research background and expertise in histopathology has led to a better understanding of pathogenesis of the chemical/drug-induced toxicity and has highlighted the value of precision cut liver and lung tissue slices as a powerful tool to predict in vivo toxicity.

Carmen Ip, B.S.
Cell Biologist

Carmen Ip obtained her B.S. in biochemistry with a minor in managerial economics from U.C. Davis. Prior to joining SRI's Toxicology Department, she worked as a research assistant in the Physiology, Anatomy, and Cell Biology Department at U.C. Davis. In addition to having a background in genetic toxicology, she is proficient in cell culture, microtiter assays, and immuno-histological staining procedures. Carmen performs all procedures required to isolate, culture, and harvest tissue slices, including sample preparation for specialized analysis. Over many months she has instructed several staff members in the techniques associated with slice preparation and culture.

Lucita Jimenez, B.A.
Biologist

Lucita graduated magna cum laude from San Jose State University, where she majored in biological science with a minor in chemistry.  Lucita applies her background in asceptic tissue culture to slice production, experiment maintenance, slice harvest, and sample preparation for our projects. With additional experience in cDNA sequencing, her research assignments at SRI also include receptor binding and functional assays to determine affinities and activity of compounds at opioid, dopamine, and serotonin receptors.

Additional Support

• Hanna Ng, Ph.D. (Genomics)
• Mary Ann Greco, Ph.D. (Proteomics)
• Lynn Suer, Ph.D. (Microbiologist)
• Ilona Berzetei-Gurske, Ph.D. (Electrophysiologist)
• Carol Green, Ph.D. (Metabolism/Pharmacokinetics)
• Hal Javitz, Ph.D. (Statistician)
• Yannick Pouliot, Ph.D. (Bioinformatics)

Principal Support

• NIH R21/33 grant awards for liver in vitro assays
• NIH R21/33 grant awards for lung in vitro assays
  
• Collaborations: NIH grants with Dr. Ralph Parchment (Wayne St. Univ., SciTech) for gastrointenstinal and cardiac (proarrhythmia) assays

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       Last Updated Jan 25, 2010