Cancer III

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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.
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How to INC MTD and DEC MED? (2)
MTD = increase selectivity. MED = increase potency
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Generic structure. Antibody. (4)
Maintains PK. Targeted at well characterised antigen. Antigen not down regulated on Ab binding. Minimal non specific binding.
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Generic structure. Linker (3)
Stable so ADC remains intact. Doesnt alter Ab PK or characteristics. Cytotoxic inactive when bound.
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Generic structure. (3)
Non-immunogenic. Non-toxic during circulation. Highly potent so 2-4 molecules sufficient.
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Bind to antigen. Ingested via endocytosis. Endosome formed. Lysosomal trafficking. Lysosomal degredation releases cytotoxic agent which then causes cell death.
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Penetration of ADC is an issue. Although they extrvasate...
as distance increases ADC penetration is impaired. Krogh Cyclinder Results.
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How can this be improved?
Finding molecule that exhibits a bystander effect.
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Current ADC's? (2)
Brentuximab Vedotin and T-DM1
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Brentuximab vedotin. (3)
Chimeric MAB. Effector is MMAE. Adverse FX: Neutropenia, N&V, resp inf.
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T-DMI (1)
Trastuzumab is MAB - treats cancer alone. HERCEPTIN.
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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
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How does this occur? (1)
Tumour cells undergo metabolic re-programming.
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Warburg effects? (3)
Damage to mitochondria. Phenotypic adaptation to hypoxia. Cancer genes shut down mitochondria due to involvment in cell death
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When inadequate O2? (4)
Glucose -(2ADP->2ATP / 2NAD+ -> 2NADH)> 2 Pyruvate -(2NADH->2NAD+)> 2 Lactate.
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What does this accomplish? (1)
Replenishes NAD+.
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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.
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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.
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Describe Lactate Dehydrogenase. (3)
Tetrameric enzyme. LDH-A: Pyr -> Lac. LDH-B: Lac -> Py
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Describe PDK1.
Controls activity of PDH which controls pyruvate entry to TCA. PDK1 phosphorylates PDH to reduced PDH activity and suppression of TCA entry
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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.
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How is OOA synthesised? (2)
Oxidation of glutamine. Glutamine is oxidised in mitochondria to alpha-ketoglutarate which enters TCA to form OOA.
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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.
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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.
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Cancer drug targets of glycolysis? (3)
PDK1, LDH-A and Modulation of NADH/NAD
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PDK1 as a drug target. (3)
Dichloroacetate targets PDK1. Shifts metabolism back to oxidation in mitochondria. DCA restores mito function therefore killing cancer cells.
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LDH-A as a target. (3)
Knockdown of LDH-A using shRNA inc mito resp and dec mito memb potential. reduces cell proliferation
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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)
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Modulation of NADH/NAD.
Likely to cause toxicity. NAD Dependant enzymes and NADH Dependant enzymes.
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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.
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NADH Dependant Enzymes.
Oxioreductases: NQO1
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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.
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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
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