Dose Response 100% 50% 0% IC50, EC50 Dose response curve.
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Transcript of Dose Response 100% 50% 0% IC50, EC50 Dose response curve.
Dose
100%
50%
0%
IC50, EC50
Dose response curve
22 Days MEK Inhibitor 22 Days Vehicle Control
Growth of Tumor Xenografts in Mice after Drug Treatment
CK19
P-H3DAPI DAPI P-ERK
CK19
DAPI P-H3
CK19
DAPI P-ERK
CK19
L3.6pl
w/o MEK-inhibitor
L3.6pl
with MEK-inhibitor
Primary tumor sections:
Drug Sensitivities:
•IC50 values of CI-1040 for 22 pancreatic cancer cell lines were measured.
•The cell lines rank from sensitive to resistant: low IC50 sensitive; high IC50 resistant
•Why is that important to know?
Patients show often various degrees of sensitivities to drugs.
It would not be smart to treat a patient with a drug if he is not sensitive enough (side effects).
It would be good to have a knowledge about drug sensivities of a patient in advance.
How can we get such a knowledge?
measuring biomarkers for drug sensitivities (gene expression profiling, comparative genomic hybridization, proteomics)
Binding of a strand of DNA to a complementary strand of DNA or RNA:
Adenine binds to Thymine
Guanine binds to Cytosine
In RNA Thymine is replaced by Uracil.
The binding or annealing of complementary strands is highly sequence specific.
Microarray technology:
Examples
Gene expression profiling
Array based comparative genomic hybridization (aCGH)
gain in the test DNA
balanced in the test DNA
loss in the test DNA
Test DNA isolated fromcancer cells(Cy3)
Reference DNAisolated fromcontrol(Cy5)
Image (CCD camera)and data analysis using software
Array CGH (aCGH): a microarray based technology
Human chromosomes become fragmentized
DNA fragments become spotted on glass slide
1 3 5 7 9 11 13 15 17 19 21X
Panc - 4.21
-1.5
-0.5
0.5
1.5
2.5
Lo
g2
Me
an
Ra
w R
ati
oExample of an aCGH profile: Array contains roughly 2500 printed DNA fragments covering the human genome at 1.4 Mbp resolution.
Ratio > 0 Tumor DNA is overrepresented: gain in copy number (amplifications)
Ratio < 0 Tumor DNA is underrepresented: loss in copy number (deletions)
Combining drug sensitivities with array CGH:
•We have measured copy number changes in 22 cell lines.
•We also determined the drug sensitivities of those cell lines to CI-1040.
Question: Can we find copy number changes that correlate with sensitivity or resistance to CI-1040?
More precise: Can we find signatures of copy number changes that characterize sensitive or resistant cell lines?
Answer: Student T-test; linear regressions
Acknowledgements:Martin McMahon (my boss)
McMahon Lab
Helen Diller Family Comprehensive Cancer Center UCSF