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4 CAN > 8 Chemotherapy MOA > Flashcards

8 Chemotherapy MOA Flashcards

1
Q

What 4 types of drugs to cancer are there?

A

molcularly targeted agents
cytotoxic chemotherapy
immune therapy
anti-angiogenesis

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2
Q

What is cytotoxic chemotherapy good at?

A

killing at least some cancers

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3
Q

Why does cytotoxic chemotherapy have a narrow therapeutic index?

A

normal cells recover from cytotoxic injury faster than cancer cells

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4
Q

What does reversible toxicity target?

A

rapidly dividing cels

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5
Q

What does reversibility reflect?

A

compartment repopulation by recruitment of resting stem cells

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6
Q

What do ‘irreversible’ cumulatic toxicites target?

A

slow growing cells

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7
Q

What problems are associated with irreversible cumulative toxicities?

A

genotoxicity

mutations (secondary malignancies)

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8
Q

In cytotoxic chemotherapy, what happens when you increase the dose?

A

increase the chances of cytotoxicity

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9
Q

What happens in pre-clinical trial phases to answer what question?

A

drug development

Is it rational to test this in humans?

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10
Q

What is investigated in phase I trials to answer what questions?

A

dose limiting toxicity

what dose to use?
Can it be used safely?

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11
Q

What is investigated in Phase II trials to answer what questions?

A

tumour response
complete response
progression-free survival

does it shrink cancers?
safety and toxciity?

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12
Q

What is investigated in Phase III trials to answer what question?

A

Overall survival
QoL

Does it out - perform standard care?

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13
Q

What defines the maximum dose?

A

level of toxicity

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14
Q

What ethics have to be acocunted for when using the absolute maximum dose?

A

13 principles of Good Clinical Practice for clinical trials

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15
Q

What is the role of p53?

A

mediates G1 and G1 cell cycle arrest

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16
Q

What are the 2 key apoptotic pathways?

A

intrinsic

extrinsic

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17
Q

What happens in the intrinsic apoptotic pathway?

A

genotoxic damage detected
cytochrome C released from mitochondria
activation of caspase 9

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18
Q

What might cancers express in the mitochondria, what does this do?

A

Bcl-2

increases apoptosis threshold

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19
Q

Name an anti-metabolite

A

5-flourouracil

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20
Q

What does 5-flourouracil do?

A

mimics structure of a pyrimidine but with a flourine atom incorporated

leads to breaks and apoptosis

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21
Q

Name 4 types of anthracyclines

A

Doxorubicin
Daunorubicin
Idarubisin
Epirubicin

22
Q

What is the anthracycline moa?

A

Topoisomerase II inhibition
DNA intercalation
ss and ds DNA breaks
Free radical formation - bind to DNA

23
Q

How are anthracyclines eliminated?

A

metabolism (aldoreductases)

biliary excretion

24
Q

What do topoisomerases do?

A

unravel DNA

25
Q

Why might you want to unravel DNA?

A

DNA repair
replication
RNA synthesis

26
Q

What are the 2 forms of topoisomerases?

A

monomeric

dimeric

27
Q

What are monomeric topoisomerases?

A

ATP independent, single nick in ds DNA

28
Q

What compounds target topoisomerase 1?

A

anthracyclines

Camptothecin analogues

29
Q

How do topoisomerase 1 targeting agents work?

A

stabilise enzyme, resulting in irreversible double stranded DNA breaks, G2 arrest, and apoptosis

30
Q

What do dimeric topoisomerases do?

A

ATP-dependent mechanism

cleaeve both strands to allow another double strand to pass through the gap

31
Q

What are the inhibitors to topoisomerase 2?

A

anthracyclines

Epipodophyllotoxins

32
Q

how do topoisomerase 2 inhibitors work?

A

inhibit relegation of broken ds DNA

result in reversible protein-linked dsDNA breaks

33
Q

Name 2 microtubule inhibitors?

A

Vinca alkaloids

Taxanes

34
Q

Name an example of a Vinca alkaloid

A

Vincritisine from periwinkle plant

35
Q

what do Vinca alkaloids do?

A

stop assembly and promote disassembly of microtubules

metaphase arrest

36
Q

Name an example of a Taxane

A

Paclitaxel from Taxus brevifolia yew tree bark

37
Q

What do taxanes do?

A

stabilise microtubules
inhibit dynamic reorganisation
sustained metaphase / anaphase block

38
Q

What do alkylating agents do?

A

leaving groups form highly polarised electrophiles
these then bind covalently with macromolecules, including DNA

may target O in purines and pyrimidines

39
Q

What similarities are there between platinum analogues and alkylating agents?

A

leaving group which interacts with macromolecules

40
Q

What do platinum analogue leaving groups do?

A

forms intra-strand adducts within DNA

41
Q

Name 2 types of platinum analogues

A

cisplatin

carboplatin

42
Q

What other effect might cytotoxic agents have pre-apoptosis?

A

cause calreticulin release

an ‘eat me’ signal

43
Q

What other effect might cytotoxic agents have during-apoptosis?

A

release ATP acting as a chemoattractant

44
Q

What might membrane damage to cancer cells cause?

A

release of HMGB1 protein, which activates the immune system by TLR

45
Q

Why do we perform chemotherapy in cycles?

A

allows normal cell compartments to recover

46
Q

What is neo-adjuvant therapy?

A

reduction in primary tumour sie pre-surgery

47
Q

What is adjuvant therapy?

A

surgeon removes primary tumour

microscopic deposits mopped up by chemo

48
Q

Why might you do neo-adjuvant therapy?

A

some tumours difficult to remove
reduces cosmetic damage
reduces probability of nearby microscopic residues

49
Q

Why might cancers be less suceptible to chemo?

A

not all tumour cells are dividing

50
Q

How does tumour size affect growth fraction?

A

bigger tumours have a lower growth fraction

51
Q

What are the aims of combination chemotherapy?

A

achieve maximum cell kill with tolerable toxicity
increase kill fraction
prevent or slow outgrowth of resistant malignant clones

4 CAN (21 decks)

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