Cancer II

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Name four types of classical anti cancer agents and how they act? (4)
Alkylating agents - add alkyl to DNA. Antimetabolites - prevents DNA synth. Anti-tumour antibiotics - intercalates DNA. Miotic Spindle poisons - Prevent miotic separation.
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Three most common forms of toxicity? (3)
Myelosuppression. GI (N&V), Skin and Hair.
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What is the therapeutic index? (1)
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What are the three portions of a anti-cancer prodrug? (3)
Trigger - Linker - Effector
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What does each do? (3)
Trigger - substrate for enzyme over expressed in tumour. Linker - once trigger activated sends electrical signal transmitted to effector via linker. Effector - cytotoxic portion of drug (only when trigger active)
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What is selectivity of these drugs determined by? (1)
These drugs act in areas with high concentrations of enzyme.
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3 Examples of anticancer pro-drugs? (3)
Protease Activated Drugs. Hypoxia Activated Drugs. Enzyme Activated Drugs.
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What is the concept of Protease Activated Prodrugs? (1)
Invasion and metastasis is a hallmark of cancer. Tumour cells secrete proteases to digest extracellular matrix - proteases.
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5 Classes of proteases? (5)
Serine, Cysteine, Theronine, Aspartic, Matrix Metalloproteinases (MMPs)
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Which is most important? (1)
MMP's. Act in invasion and angiogenisis - 2 hallmarks.
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Failed attempt at targeting MMP? (1)
MMP inhibition - caused toxicities and cancer had already spread by time treatment occurred.
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What are MMP's? (3)
Zinc dependant enzymes. In normal tissue kept in check by Tissue inhibitors of MMP (TIMPs). Over expressed in cancer.
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Describe the structure of a protease activated prodrug?
End Cap - prevents peptide digestion by exopeptidases. Peptide - Trigger (MMP substrate). Drug Cytotoxic agent - only restriction is must be inactive when linked with peptide.
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Example? (1)
Bradford Smart Bomb
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Describe design of BSB? (4)
ICT2588 - MMP Substrate - Tyrosine Linker - Colchicine
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Why is colchicine not used as a cytotoxic? (1)
Low dose treats gout. Can't reach high enough tolerated dose to exhibit anti cancer action. This is solved with selectivity.
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How is BSB administered?
Intra-peritoneal route.
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Results of BSB trials?
cure in 5/8 mice in combo with doxorubicin. Activity against range of tumour types.
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Summaries Protease Activated Prodrugs. (6)
Invasion and metastasis is hall mark of cancer. Inhibition of MMP didnt work - toxicity and tumour had spread by time of detection. Utilise MMP to activate pro-drug. Colchicine linked with MMP activated trigger widens TI. ICT2588 scheduled for trial
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Describe the physiological microenvironment of tumours. (4)
Gradients of O2 tension, nutrients, pH, catabolites. Subregional areas of hypoxia.
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How does hypoxia lead to a more aggressive phenotype (7)
Promotes genetic and epigenetic changes. Changes in apoptosis. Shift to glycolytic metabolism. Up-regulates survival factors. Production of enzymes mediating invasiveness. Stimulates angiogenic signals. Promotes epithelial to mesenchymal transition.
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Concept of HAPs?
An inactive compound is metabolically converted to an active drug.
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Selectivity of HAPs is determined by? (3)
Reductase enzymes. Ability of molecular oxygen to reverse reaction. Ability of effector to be released and kill cells.
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Hypoxia in tumours is associated with poor response to?
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How is hypoxia in tumours detected?
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Design features of an optimised HAP? (6)
Inactive in normoxia and therefore non-toxic in normal tissues. Requiring extreme hypoxia for activation. Metabolically stable. Adequate PK and good tissue penetration. Kills non-dividing as well as dividing. Exhibits ideal bystander effect.
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New hope for HAPs? (2)
TH-302. (Br-IPM metabolite that causes DNA damage)
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Describe Th-302 metabolism. (2)
Normoxia: Converted to radical anion but then reverts in presence of O2. Hypoxia: Further fragmentation occurs to hydroxyl amine and Br-IPM.
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Which enzyme is responsible? (1)
1e' reductases ( NADPH CYP450 Reducatase)
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LC50 of TH302 in various O2 concs. (1)
N2:0.1 O2: 0.1% - 1 0.6% - 5 10% - 25 Air: 55
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When double strand breaks are cuased in DNA by TH-302...
H2AX becomes phosphorylated on serine 139 to become gamma H2AX.
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What does staining show? (1)
Staining of gamma H2AX +ve colocalises with Pimonidazole
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Other good factors of TH-302? (2)
Good synergy with other compounds. Shows Bystander effect as gamma H2AX staining spreads outwards by 24hrs.
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Example of Enzyme activated prodrugs? (2)
EO9: an analogue of Mitomycin C
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EO9 is a substrate for? (3)
NQO1 - 2e' reductase. CYP450 and CY B5 - 1e' reductase
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How does it damage DNA? (1)
Single strand breaks.
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How is EO9 reversed? (1)
Oxygen - can target hypoxic tissues.
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Describe EO9 metabolism. (4)
EO9 -(1e')> Semiquinone -(1e')> Hydroquinone. Or straight to Hydro by 2e'. Reversible in O2
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What is the limiting toxicity of EO9? (1)
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Reasons EO9 failed? (3)
Neither enzymology or hypoxia measured. Administered as single agent - hypoxic target of aerobic cells is more effective using combo of two. Should have shown some activity in big sample > Investigate drug delivery.
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2 Key factors control DD. (2)
PK Profile. Ability of compounds to extravasate and penetrate through a vascular tissue.
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PK of E09? (3)
Short half life. Unable to penetrate multi cell layers rapidly. Within PK lifespan only penetrate few uM of space from vessel.
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EO9 vesically would?
Circumvent delivery problem. Retention in bladder would enhance drug penetration. Drug reaching systemic circulation would be rapidly cleared lowering toxicity.
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Where would this work? (3)
Bladder Cancer (5th most common in UK) 70% have T1 tumours . 83.4% had strong NQO1.
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How is this measured? (1)
Marker lesion concept: all tumours removed at surgery except for ONE which remained in situ to assess response.
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Phase II trial results? (3)
46 pts. 30 showed complete response. EO9 delayed tumour recurrence. Marker Lesion design.
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Loco-regional therapies? (2)
good PK not needed. Poor PK could be advantage if systemic - cleared quickly.
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Card 2


Three most common forms of toxicity? (3)


Myelosuppression. GI (N&V), Skin and Hair.

Card 3


What is the therapeutic index? (1)


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Card 4


What are the three portions of a anti-cancer prodrug? (3)


Preview of the front of card 4

Card 5


What does each do? (3)


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