Cancer III

What is ADC? (2)
Antibody-Drug Conjugates. By linking to an antibody that recognises an antigen on tumour tissue, the cytotoxic agent is only delivered to the tumour.
1 of 32
How to INC MTD and DEC MED? (2)
MTD = increase selectivity. MED = increase potency
2 of 32
Generic structure. Antibody. (4)
Maintains PK. Targeted at well characterised antigen. Antigen not down regulated on Ab binding. Minimal non specific binding.
3 of 32
Generic structure. Linker (3)
Stable so ADC remains intact. Doesnt alter Ab PK or characteristics. Cytotoxic inactive when bound.
4 of 32
Generic structure. (3)
Non-immunogenic. Non-toxic during circulation. Highly potent so 2-4 molecules sufficient.
5 of 32
Bind to antigen. Ingested via endocytosis. Endosome formed. Lysosomal trafficking. Lysosomal degredation releases cytotoxic agent which then causes cell death.
6 of 32
Penetration of ADC is an issue. Although they extrvasate...
as distance increases ADC penetration is impaired. Krogh Cyclinder Results.
7 of 32
How can this be improved?
Finding molecule that exhibits a bystander effect.
8 of 32
Current ADC's? (2)
Brentuximab Vedotin and T-DM1
9 of 32
Brentuximab vedotin. (3)
Chimeric MAB. Effector is MMAE. Adverse FX: Neutropenia, N&V, resp inf.
10 of 32
T-DMI (1)
Trastuzumab is MAB - treats cancer alone. HERCEPTIN.
11 of 32
What is the Warburg effect? (2)
Most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria
12 of 32
How does this occur? (1)
Tumour cells undergo metabolic re-programming.
13 of 32
Warburg effects? (3)
Damage to mitochondria. Phenotypic adaptation to hypoxia. Cancer genes shut down mitochondria due to involvment in cell death
14 of 32
When inadequate O2? (4)
Glucose -(2ADP->2ATP / 2NAD+ -> 2NADH)> 2 Pyruvate -(2NADH->2NAD+)> 2 Lactate.
15 of 32
What does this accomplish? (1)
Replenishes NAD+.
16 of 32
Why is Warburg effect wrong? (2)
Tumours do undergo glycolysis but require high conc of glucose. Mitachondiral activity is not completely abolished - instead it produces anabolic precursors for cell proliferation.
17 of 32
Key features of Warburg effect? (5)
Glycolysis: major source of ATP and growth intermediates. Glucose transport is enhanced. Lactate dehydrogenase expression is inc. PDK1 activity is increased. TCA/OXPHOS energy production is low.
18 of 32
Describe Lactate Dehydrogenase. (3)
Tetrameric enzyme. LDH-A: Pyr -> Lac. LDH-B: Lac -> Py
19 of 32
Describe PDK1.
Controls activity of PDH which controls pyruvate entry to TCA. PDK1 phosphorylates PDH to reduced PDH activity and suppression of TCA entry
20 of 32
TCA in cancer. (5)
Occurs in mitochondria. Pyruvate->ACoA->Condenses with OOA->Generates Citrate. PDK1 reduces ACoA avail. Kreb cycle therefore used to generate lipids. Citrate cleaved outside mitochon to form ACoA.
21 of 32
How is OOA synthesised? (2)
Oxidation of glutamine. Glutamine is oxidised in mitochondria to alpha-ketoglutarate which enters TCA to form OOA.
22 of 32
How is glycolysis good for cancer cells? (3)
Generates 2 ATP rapidly, 2 NADH, 2 Pyruvate and 1 Glucose. Total ATP yield is more than 2 as NADH enters to aid TCA. Provides intermediates for growth.
23 of 32
Why is glycolysis favoured even in O2 presence? (3)
Enables hypoxic survival. Maintenence and regulation of biosynthesis. Lactate secretion creates tumour microenvironment which favours growth - acidification degrades EXM and aids invasion.
24 of 32
Cancer drug targets of glycolysis? (3)
PDK1, LDH-A and Modulation of NADH/NAD
25 of 32
PDK1 as a drug target. (3)
Dichloroacetate targets PDK1. Shifts metabolism back to oxidation in mitochondria. DCA restores mito function therefore killing cancer cells.
26 of 32
LDH-A as a target. (3)
Knockdown of LDH-A using shRNA inc mito resp and dec mito memb potential. reduces cell proliferation
27 of 32
Suppression of LDH-A causes?
p53 dependant NADH:NAD inc. Reduction in SIRT1 activity (due to lower NAD). Inc in eO9 activity (due to inc NADH)
28 of 32
Modulation of NADH/NAD.
Likely to cause toxicity. NAD Dependant enzymes and NADH Dependant enzymes.
29 of 32
NAD Dependant Enzymes. (3)
Sirtuins: NAD Dependant histone deacytelases implicated in n.o cell survival processes. SIRT 1 cancer specific sirtuin. PARP: NAD Dependant repair protein that protects cell from chemo.
30 of 32
NADH Dependant Enzymes.
Oxioreductases: NQO1
31 of 32
Outline COMET assay.
Single cells encapsulated in low mp agarose on glass slide. Cells lysed in high salt detergent. Memb diffuse into agar. DNA remains exposed to alkaline ph>13 becomes single strand. Electrophoresis 25-30 min. Slides neutralised and DNA stained.
32 of 32

Other cards in this set

Card 2


How to INC MTD and DEC MED? (2)


MTD = increase selectivity. MED = increase potency

Card 3


Generic structure. Antibody. (4)


Preview of the front of card 3

Card 4


Generic structure. Linker (3)


Preview of the front of card 4

Card 5


Generic structure. (3)


Preview of the front of card 5
View more cards


No comments have yet been made

Similar Other resources:

See all Other resources »See all Drug Design and Development 2 resources »