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CAN > L08: Chemotherapy Mechanims Of Action > Flashcards

L08: Chemotherapy Mechanims Of Action Flashcards

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1
Q

What are the 3 main modalities of treating cancer

A

Surgery
Radiotherapy
Chemotherapy

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2
Q

What treatment modality does cytotoxic drugs belong to

A

Chemotherapy

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3
Q

What is the therapeutic index of cytotoxic drugs like

A

Narrow

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4
Q

What does a narrow therapeutic index mean

A

Agents that target the diving cells (tumour cells) can affect normal healthy cells that are also dividing

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5
Q

Can normal cells recover from cytotoxic injury

A

Yes

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6
Q

What structures and cells does cytotoxic drugs affect

A 
Bone marrow 
GIT
Germinal epithelium 
Lymphoid tissue 
Hair follicles
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7
Q

Are cytotoxic drugs targeted drugs

A

No

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8
Q

If cytotoxic drugs are not targeted drugs what vital organs can they affect

A

Kidney
Nerves
Heart
Lungs

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9
Q

What can the affect of cytotoxic drugs on these organs cause

A

Renal failure
Nerve damage
Heart failure
Lung fibrosis

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10
Q

What does genotoxic mean

A

Toxic (Damaging) to DNA

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11
Q

Are cytotoxic drugs genotoxic

A

Yes

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12
Q

If cytotoxic drugs are genotoxic what can this lead to

A

Mutations

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13
Q

What can mutations in people using cytotoxic drugs result in overall

A

Secondary malignancy

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14
Q

When increasing the dose of cytotoxic drugs to get an anti cancer effect what chance also increases

A

Toxicity

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15
Q

What are the 10 hallmarks of cancer

A

1) sustaining proliferative signalling
2) evading growth suppressors
3) enable replicative immortality
4) resisting cell death
5) activating invasion and metastasis
6) inducing angiogenesis
7) deregulating cellular energetic
8) avoiding immune destruction
9) tumour promoting inflammation
10) genome instability and mutation

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16
Q

If we know the hall marks of cancer what can we do

A

Molecular target and engineer drugs that hit those targets

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17
Q

Which patients is molecular targeted drugs likely to work on

A

Specific patients based on the molecular properties of cancer

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18
Q

Compare cytotoxic drugs and molecules targeted drugs in terms of the cancer they can target and toxicity

A

Cytotoxic drugs: effective against a broad number of cancer, but toxic
Molecular targeted drugs: effective against specific cancer and less toxic

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19
Q

What does cytotoxic drugs work on in the cell

A

Cell cycle

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20
Q

How do different agents work on the cell cycle

A

Different agents have different effects on the cell cycle

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21
Q

Name the different cytotoxic drugs that we use

A 
Micro-tubule inhibitors 
Topoisomerase inhibitors 
Alkylating agents 
Anti-metaboliities
Platinum analogues
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22
Q

What is p53

A

A tumour suppressor gene

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23
Q

When there is cytotoxic damage what happens to P53

A

Plays a role in detecting cytotoxic and genotoxic damage then transcriptional activator to mediate G1, G2 cell cycle arrest or apoptosis

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24
Q

In many cancers what is p53 like

A

Lost or mutated so it is inactive

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25
In chemotherapy what are we trying to trigger
Apoptosis
26
What are the 2 pathway of apoptosis
Intrinsic pathway | Extrinsic pathway
27
What does the intrinsic pathway involve
1) genotoxic damage is detected 2) cytochrome c is released from the mitochondria 3) cytochrome c binds to a path 1 activator 4) caspase 9 is activated with results in apoptosis
28
What does the extrinsic pathway involve
1) pathway relies on tumour necrosis family receptor (TNFR) | 2) TNFR activates caspase that initiates apoptosis
29
Which pathway does agents select for apoptosis
Different agents select different pathways either intrinsic or extrinsic
30
What protein does some cancer release that increases the threshold for apoptosis
BCL-2
31
What has to happen for the intrinsic pathway to become activated
DNA damage from chemotherapy
32
What detects the cellular stress in the intrinsic pathway to activate it
P53 detect DNA damage and activates the intrinsic pathway
33
What determines the activation of the extrinsic pathjwaty
Condition in the extracellular environment
34
What phase of the cycle does anti-metabolites work at
DNA synthesis (s phase)
35
Give an example of a anti-metabolite drug
5-flurouracil
36
What structure does 5-flurouracil have
Pyramidine with flurocine attached to it
37
In a normal cell how are nucleotides metabolised e.g thymidine
1) DUMP acquire methyl group via thymidine synthetase and folic acid to become DTMP 2) DTMP becomes phosphorylated into DTDP 3) DTDP becomes phosphorylated into DTTP i.e thymidine 4) thymidine becomes incorporated into DNA during DNA synthesis
38
How does 5fluro-uracil act
1) 5FU becomes incorporated to DUMP to from to Fluorodeoxyuridine monophosphate (FDUMP) 2) FDUMP inhibits thymidine synthetase 3) thymidine cannot be produced and DNA synthesis cannot occur 4) apoptosis occurs
39
What are the actions of anthracyclines
- inhibit topoisomerase 2 - induce free radical formation that bind to dna - DNA intercalaton for DS or SSDNA break
40
Name an example of topoisomerase 2 inhibitor
Anthracycline
41
Name examples of anthracycline drugs
Doxorubicin
42
By blocking topo-isomerase what does it prevent
Uncoiling of DNA to stop replication and gene expression
43
How do athracycline block the action of topoisomerase 2
By binding to the enzyme topoisomerase 2
44
What are the 2 forms of topoisomerase inhibitors
Topoisomerase 1 | Topoisomerase 2
45
What is the monomeric form
ATP independent
46
What is the normal action of topoisomerase 1
Cleave one strand of the dna
47
Name examples of topoisomerase 1 inhibitor
Anthracylcines | Camptothecin analogues
48
What are dimer forms
Atp dependent
49
What is the normal action of topoisomerase 2
Bind to double stranded dna to cleave both strands
50
Name examples of topoisomerase 2 inhibitors
Anthracycline | Epipodophylotoxins
51
What does anthracylines have
Toxicity
52
What can toxicity of anthracylines cause
``` Myelosupression GIT Local tissue damage Alopecia Cardio toxicity ```
53
What do microtubules form
Cytoskeleton of cells
54
What are microtubules involved in
``` Mitotic spindles Chemotaxis Membrane scaffolding Intracellular transport Signalling ```
55
When microtubules inhibitors inhibit microtubules what does it impair
The normal functions of microtubules
56
What are the 2 groups of microtubules inhibitors
Vinca alkaloids | Taxanes
57
How do vinca alkaloids functions
Stop assembly and dissembley of microtubules i.e stop the production/formation of new microtubules (destabilises)
58
What cell cycle phase does vinca alkaloids work in
M phase (arrest it)
59
What toxicity does vinca alkaloids show
Neurones GI Marrow
60
How do taxanes function
Stabilise microtubules and inhibit dynamic reorganisation i.e break microtubules that have already formed (stabilises)
61
At what cell cycle phase does taxanaes work at
Anaphase and metaphase
62
What toxicity does taxanes show
Neurones | Marrow
63
How do alkaylting agents work
Bind to guanine crosslink DNA strands
63
When alkylating agents bind to DNA what do they affect
DNA translation and transcription
64
Name another group of drugs that are similar to alkalyting agents
Platinum analogues
65
How does platinum analogues function
Charged particle binds convently to macromolecules e.g dna
67
What does platinum analogues form
Intra stand DNA adducts
68
Name an example of a platinum analogue
Cis platin
69
What do some chemotherapy agents cause the release of to signal an eat me signal to the immune system so the cell is engulfed
Calreticulin
70
During apoptosis what can chemotherapy agents cause the releases of so dendritic cells are attracted to the site and makes the tumour to become engulfed
ATP
71
During secondary necrosis what can chemotherapy agents cause the release of
HMGB1
72
What does HMBG1 cause
Attraction of dendritic cells to the tumour
73
Therefore apart from killing the cells what other role does chemotherapy agent shave
Exposing the cells to the immune system for further killing of cells
74
What are the 4 clinical uses of chemotherapy
Primary chemotherapy Neo-adjuvant Adjuvant Chemoradiotherapy
75
What is primary chemotherapy
The main treatment of cancer so the tumour shrinks and goes away
76
What is neo adjuvant chemotherapy
To reduce the size of the tumour before surgery
77
What is adjuvant chemotherapy
Chemotherapy that is used after the surgery to remove microscopic tumour and prevent relapse of cancer
78
What is chemo radiotherapy
Ionizing therapy is the primary treatment but giving additional cytotoxic chemotherapy makes it sensitiser for radiation
79
What does chemotherapy target
Dividing cells
80
Can a proportion of tumour cells be non diving cells
Yes
81
Is a proportion of tumour cells are non dividing what happens to the susceptibility of the cell to chemotherapy
Decreases
82
What happens to the cells in cell division as the tumour size increases
Decreases
83
What other feature does large tumour have that make is less resistant to chemotherapy
Drug resistant clones
84
Therefore overall why are large tumours resistant to chemotherapy
They have resistant clones | They have more cells that are non dividing
85
To kill cancer cells as much as possible what do we need the doses of cytotoxic drugs
Close to tolerated dose
86
To squeeze cycles together what agent can we use in chemotherapy
GSF
87
What does GSF do
Increase neutrophil recovery rate between the cycles of chemotherapy and the bone marrow recovers faster

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