COG U01 U S Food and Drug Administration Home COG U01 美国食品与药物管理局.ppt

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COG U01 U S Food and Drug Administration Home COG U01 美国食品与药物管理局.ppt

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Advantages and Limitations of Cell Culture Models in Pediatric Drug Development Peter C. Adamson, M.D. The Children’s Hospital of Philadelphia Clonogenic Assay Primary Bioassay of Human Tumor Stem Cells* Tumor stem cells are cell renewal source and serve as seed of metastatic spread Cytotoxicity in clonogenic assay proportional to cytotoxicity in vivo Tritiated Thymidine Incorporation 3H-TdR measures cells in S-phase Quantifies cell number as cpm Historical in vitro Assays Clonogenic Assay Labor intensive Not readily amenable to high throughput 3H-TdR Limitations of using radioactivity Non-clonogenic method Non-clonogenic Assays MTT Assay Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxcity assays* Non-Clonogenic Assays MTT XTT SRB Trypan Blue DiscAssay FDA TACs Hoechst WST-1 Acid Phosphatase DIMScan MTS Brd-U Luminescent-ATP Non-Clonogenic Assays Use of Cell Culture Models Drug discovery Limitations of Cell Culture Models Cell lines undergo transformation to allow for in vitro growth Drugs may require metabolic activation or have active metabolites Potential differences in drug exposure Protein binding Drug disposition not modeled Differences in tumor micro-environment Lack of vascularization Hypoxia Other limitations… Advantages of Cell Culture Models Not labor intensive Relatively low cost Moderate throughput capabilities Ability to study multiple cell lines Ability to study multiple combinations of drugs Only system that mathematically determines synergy, additivity, and antagonism Example: Determination of Synergy Problems with the “addition” method Drug A 25% cell kill Drug B 25% cell kill Drug A + Drug B 50% cell kill - synergy? It’s not that simple Drug A 70% cell kill Drug B 70% cell kill Drug A + Drug B = 140% cell kill? Median Effect Model Example: Activity in Pediatric Tumors BMS 247550 is an analog of epothilone B that binds tubulin, stabilizes mictrotubules by inhibiting tubulin depolymeri