stem cells are cell renewal source and serve as
seed of metastatic spreadCytotoxicity in clonogenic assay proportional to cytotoxicity in vivo
*Hamburger AW, Salmon SE. Science, 197 (4302) 461-463; 1977.
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Презентация на тему Advantages and Limitations of Cell Culture Models in Pediatric Drug Development
Содержание
- 2. Clonogenic AssayPrimary Bioassay of Human Tumor Stem
- 3. Tritiated Thymidine Incorporation3H-TdR measures cells in S-phaseQuantifies cell number as cpm
- 4. Historical in vitro AssaysClonogenic AssayLabor intensiveNot readily amenable to high throughput3H-TdRLimitations of using radioactivityNon-clonogenic method
- 5. Non-clonogenic AssaysMTT AssayRapid colorimetric assay for cellular
- 6. NCI 60-Cell Line ScreenLeukemiaNSCLCSmall Cell ColonCNSMelanomaOvarianRenalNCI 60 Cell Line Screen
- 7. Non-Clonogenic AssaysMTTXTTSRBTrypan BlueDiscAssayFDATACs HoechstWST-1 Acid PhosphataseDIMScanMTSBrd-ULuminescent-ATP
- 8. Non-Clonogenic AssaysNon-clonogenic assay ≈Clonogenic assay ≈Viable cell number ≈In vivo cell growth ≈Tumor growth in patient
- 9. Use of Cell Culture ModelsDrug discovery Cellular
- 10. Limitations of Cell Culture ModelsCell lines undergo
- 11. Advantages of Cell Culture ModelsNot labor intensiveRelatively
- 12. Example: Determination of SynergyProblems with the “addition”
- 13. Median Effect Model
- 14. Example: Activity in Pediatric TumorsBMS 247550 is
- 15. BMS 247550: Pre-clinical ActivityFox, Stover, Widemann, Fojo, Balis (AACR 2003)
- 16. Example: Integration of New Agents
- 17. Asparaginase + 506UNelarabine --> Asn [-]Asn [-]
- 18. Perspectives on Cell Culture ModelsIn vitro models
- 19. Скачать презентацию
- 20. Похожие презентации
Clonogenic AssayPrimary Bioassay of Human Tumor Stem Cells*Tumor stem cells are cell renewal source and serve as seed of metastatic spreadCytotoxicity in clonogenic assay proportional to cytotoxicity in vivo*Hamburger AW, Salmon SE. Science, 197 (4302) 461-463;
![Asparaginase + 506UNelarabine --> Asn [-]Asn [-] --> Nelarabine% SurvivalJayaprakash, Adamson, Lampkin,](/img/tmb/15/1443129/98621e3a1ae4b603b9f0ae6cc8630693-720x.jpg "Advantages and Limitations of Cell Culture Models in Pediatric Drug Development")
Слайд 2
Clonogenic Assay
Primary Bioassay of Human Tumor Stem Cells*
Tumor
Cytotoxicity in clonogenic assay proportional to cytotoxicity in vivo
Слайд 3
Tritiated Thymidine Incorporation
3H-TdR measures cells in S-phase
Quantifies cell
number as cpm
Слайд 4
Historical in vitro Assays
Clonogenic Assay
Labor intensive
Not readily amenable
to high throughput
3H-TdR
Limitations of using radioactivity
Non-clonogenic method
Слайд 5
Non-clonogenic Assays
MTT Assay
Rapid colorimetric assay for cellular growth
and survival: application to proliferation and cytotoxcity assays*
*Mossman
T. J Immunol Meth 1983;65:55-63.
Слайд 6
NCI 60-Cell Line Screen
Leukemia
NSCLC
Small Cell
Colon
CNS
Melanoma
Ovarian
Renal
NCI 60 Cell
Line Screen
Слайд 7
Non-Clonogenic Assays
MTT
XTT
SRB
Trypan Blue
DiscAssay
FDA
TACs Hoechst
WST-1
Acid Phosphatase
DIMScan
MTS
Brd-U
Luminescent-ATP
Слайд 8
Non-Clonogenic Assays
Non-clonogenic assay ≈
Clonogenic assay ≈
Viable cell number
≈
In vivo cell growth ≈
Tumor growth in patient
Слайд 9
Use of Cell Culture Models
Drug discovery
Cellular pharmacology
Study mechanism of action
Study drug resistance
As pediatric
tumor modelsDrug activity
Dose (concentration)-schedule dependence
Drug combinations
Слайд 10
Limitations of Cell Culture Models
Cell lines undergo transformation
to allow for in vitro growth
Drugs may require metabolic
activation or have active metabolitesPotential differences in drug exposure
Protein binding
Drug disposition not modeled
Differences in tumor micro-environment
Lack of vascularization
Hypoxia
Other limitations…
Слайд 11
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 drugsOnly system that mathematically determines synergy, additivity, and antagonism
Слайд 12
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?
Слайд 14
Example: Activity in Pediatric Tumors
BMS 247550 is an
analog of epothilone B that binds tubulin, stabilizes mictrotubules
by inhibiting tubulin depolymerization, blocks mitosis and causes apoptosis.BMS 247550 is cytotoxic in taxane resistant tumors and tumor cell lines expressing the multidrug resistance phenotype (MDR).
Fox, Stover, Widemann, Fojo, Balis (AACR 2003)
Слайд 17
Asparaginase + 506U
Nelarabine --> Asn [-]
Asn [-] -->
Nelarabine
% Survival
Jayaprakash, Adamson, Lampkin, Berg, Balis, Fox (AACR 2004)
Слайд 18
Perspectives on Cell Culture Models
In vitro models are
a cost efficient method to search for activity, but
mechanistic based approaches likely will have higher yieldIn vitro models can further our understanding of drug action in pediatric tumors
Moderate throughput is advantageous, especially when studying drug combinations
