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Oncology > Chapter 3- Threadgill > Flashcards

Chapter 3- Threadgill Flashcards

1
Q

What is an antimetabolite?

A

compounds structurally similar to endogenous molecules (e.g. Nitrogenous bases of DNA) that therefore mimic their role and inhibit nucleic acid synthesis (they are usually inhibitors of enzymes)

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2
Q

The enzymes that antimetabolites inhibit are involved in what?

A

DNA biosynthesis

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3
Q

What enzyme converts L-serine to glycine in the folate cycle

A

Serine hydroxymethyltransferase (SHMT)

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4
Q

Name three enzymes in the folate cycle

A

1) Serine hydroxymethyltransferase
2) thymidylate synthetase
3) dihydrofolate reductase

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5
Q

In the folate cycle what does dihydrofolate reductase convert?

A

Dihydrofolate to tetrahydrofolate in a oxidation step (NADPH -> NADP+)

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6
Q

What does the enzyme thymidylate synthetase convert and with what cofactor

A

5,10-CH2-tetrahydrofolate to dihydrofolate (dUMP to dTMP)

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7
Q

How does methotrexate work

A

Analogue of dihydrofolate so binds to dihydrofolate reductase and enter cell through reduced folate carrier, within the cell it gets polyglutamylated to be retained in the cells

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8
Q

What’s often given with methotrexate to rescue normal cells

A

Leucovorin (folate)

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9
Q

List 3 ways people can become resistant to MTX

A

1) mutations to dihydrofolate reductase enzyme altering binding site
2) efflux pump (p-gp)
3) mutations in reduced folate carrier

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10
Q

Name 4 lipophilic antifolate antimetabolites

A

Pyrimethamine
Methylbenzoprim
Piritrexim
Nolatrexed

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11
Q

What is nolatrexed and what is it licensed to treat

A

Lipophilic inhibitor of dihydrofolate reductase and thymidylate synthetase in the folate cycle, licensed in liver cancer

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12
Q

What are pemetrexed and raltitrexed?

A

Antifolate antimetabolites they are inhibitors of thymidylate synthetase

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13
Q

How does 5-FU and FdURD work

A

Pyramiding antagonist antimetabolites–> they prevent the beta-elimination in the mechanism of Thymidylate synthetase mechanism due to the fluorine being so electronegative, the enzyme then can’t prosecute dihydrofolate and is broken down instead

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14
Q

Is 5-FU a prodrug?

A

Yes

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15
Q

Name three antimetabolites that are classed as pyrimidine antagonists

A

5-FU
FdURD
Azacytidine

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16
Q

How does azacytidine work

A

Mimics cytidine, is a pro drug that’s phosphorylated to azacytidine triphosphate and incorporated into RNA making it unstable and decomposes causing damage to RNA

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17
Q

Name 3 purine antagonists

A

6-mercaptipurine
Thioguanine
Tiazofurin

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18
Q

Name a purine antagonist antimetabolite that’s withdrawn from clinic due to toxicity

A

Tiazofurin

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19
Q

TAD is from what drug and how does it inhibit biosynthesis

A

Is from tiazofurin, it mimics structure of NAD+ so prevents binding of this

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20
Q

How does 6-mercaptopurine and 6-thioguanine work?

A

Metabolised:
6-MP -> thio-IMP
6-TG-> thio-GMP
Both inhibit by binding at purine binding site

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21
Q

Tiazofurin, 6-mercaptopurine and 6-thioguanine all inhibit the synthesis of what?

A

Guanosine-5’-monophosphate (GMP)

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22
Q

Thio-IMP is a metabolite of what antimetabolite and what enzyme does it inhibit

A

6-mercaptopurine

Inhibits adenylo-succinate synthetase

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23
Q

TAD from what drug inhibits what enzyme

A

Tiazofurin

Inhibits IMP dehydrogenase by binding at NAD+ binding site

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24
Q

Thio-IMP and thio-GMP inhibit what enzyme and by binding at what site

A

IMP dehydrogenase through binding at the purine binding site

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25
Q

6-mercaptopurine looks like what?

A

Hypoxanthine

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26
Q

Thioguanine looks like what

A

Guanine

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27
Q

Explain the activation of purine analogues

A

6-MT -> Thio-IMP
6-thioguanine -> thio-GMP
(Through enzyme HPRT)

Thio-GMP –> thio-GTP (TG-RNA)
Thio-GMP –> thio-dGTP (TG-DNA)

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28
Q

What’s the relevance of sulphur (instead of oxygen) on 6-MP and 6-TG

A

Can’t hydrogen bond as not negative enough (unlike oxygen)

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29
Q

On TAD (active metabolite of tiazofurin) what’s the relevance of the thiol (S) in place of the positive nitrogen on NAD+

A

It can’t accept electrons so can’t get involved in OILRIG reactions

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30
Q

Thio-IMP inhibits two enzymes in the biosynthesis of GMP what are they

A

Adenylo-succinate synthetase

IMP dehydrogenase

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31
Q

Pathways to make GMP

A

IMP-> AMP

IMP-> XMP -> GMP

32
Q

Name three antimetabolites that are sugar-modified nucleosides

A

Cytarabine (Ara-C)
Fludarabine
Gemcitabine

33
Q

What is cytarabine and how does it work

A

Antimetabolites- sugar modified nucleoside, converted to triphosphate and inhibits DNA polymerase as is an analogue of dCTP

34
Q

How does fludarabine work and what is it

A

Antimetabolites- sugar modified nucleoside that gets converted to triphosphate that inhibits DNA polymerase as is an analogue of dATP

35
Q

List the order of products in the gemcitabine (F2dC)mechanism

A

F2dC
F2dCMP
F2dCDP
F2dCTP

36
Q

List the enzymes in order of involvement in the gemcitabine mechanism

A

Deoxycytidine kinase
UMP/CMP kinase
NDP kinase

37
Q

F2dCDP inhibits what two enzymes

A

CTP synthase

Ribonucleotide reductase

38
Q

What is the role of microtubules

A

Responsible for maintaining the structure of the cell and for separating the sets of chromosomes during mitosis

39
Q

Name the 5 steps of mitosis (M phase)

A 
Prophase 
Prometaphase 
Metaphase 
Anaphase 
Telophase
40
Q

What happens in prophase

A

1) Chromosomal material condenses to form a compact mitotic chromosome
2) cytoskeleton is disassembled and mitotic spindles assembled
3) nuclear envelope dispersed

41
Q

What happens in prometaphase

A

Microtubules attach to the centromeres of the chromosomes

42
Q

What happens in metaphase

A

Chromosomes align along metaphase plate

43
Q

What happens in anaphase

A

Centromeres and chromosomes separate, spindle poles move further apart

44
Q

What happens in telophase

A

Nuclear envelope assembles

45
Q

What’s a kinetochore

A

Bit of microtubule that attaches to chromosome

46
Q

What’s the spindle pole

A

Position to which the chromosomes are to be pulled

47
Q

What’s the kinetochore microtubule

A

Bit that anchors the chromosomes to the centre of the spindle pole

48
Q

What’s the astral microtubules

A

Anchor spindle poles to membrane of the cell (one at each end)

49
Q

What is a microtubule made up of?

A

Tubulin dimers

50
Q

What are tubulin dimers made up of

A

One alpha and one beta subunit

51
Q

Microtubules are in what with individual tubulin dimers

A

Dynamic equilibrium

52
Q

How do mitotic spindle poisons principally work

A

Interfere with the dynamic equilibrium between microtubules and individual tubulin dimers

53
Q

Name four vinca alkaloids

A

Vincristine
Vinblastine
Vinorelbine
Vindesine

54
Q

Name two taxols

A

Paclitaxel (taxol)

Docetaxel (taxotere)

55
Q

How does taxol and its derivatives work

A

Bind to taxol-binding site on the inside surface of microtubule preventing disassembly = concentration of tubulin dimers decreases = new microtubules cannot form and inappropriate microtubules remain

56
Q

Problems with taxol and it’s derivatives

A

Very insoluble given IV
Hypersensitivity reactions due to excipients
Correlation between making more soluble and reducing activity

57
Q

Which is better: paclitaxel or docetaxel

A

Docetaxel (semi-synthetic) slightly better activity and wider spectrum of activity

58
Q

What does taxol come from and why is this source a problem

A

Pacific yew- takes 3 trees to make one course of treatment for the patient

59
Q

How do colchicine like drugs work

A

Bind to colchicine binding sites on the beta-tubulin subunits disfavouring assembly of protofilaments, also bind to colchicine binding sites on beta-tubulin in microtubules disfavouring disassembly of inappropriate microtubules

60
Q

Name two colchicine like drugs

A

Colchicine

Combretastatin A-4

61
Q

Name an enzyme that’s involved in repairing alkylation (methylation) at O6-guanine

A

MGMT

62
Q

Name two drugs that inhibit the repair enzyme MGMT

A

O6-benzylguanine

Patrin

63
Q

PARP-1 is essential for what types of repair

A

Nucleotide excision repair

Single strand break repair

64
Q

Name two PARP-1 inhibitors and what’s the rationale behind them?

A

Olaparib
Veliparib

Want to stop the repair before it goes in to the cell cycle

65
Q

What is XL844?

A

Small molecule potent inhibitor of checkpoint kinases (CHK1 &CHK2) which induce cell cycle arrest

66
Q

What is DNA dependent protein kinase (DNAPK) and what’s its role

A

Enzyme that is required for non-homologous end joining (NHEJ) which rejoins double strand breaks

67
Q

Example drug that inhibits DNA dependent protein kinase

A

NU7441

68
Q

List four was tumours have poor vascular structure

A

Disorganised network
Vessel walls not well formed
Leaky
High interstitial pressure

69
Q

Three zones of a tumour

A

1) nectrotic region
2) hypoxic region
3) Oxic region

70
Q

Why are hypoxic tissues less sensitive to radiotherapy

A

Radiotherapy requires oxygen

71
Q

Name two radiosensitising drugs

A

Electron-affinic radiosensitisers:

1) pimonidazole
2) etanidazole

72
Q

Name 4 hypoxia-selective drugs

A

Nitroimidazoles
Mitomycin C
Tirapazamine
AQ4N

73
Q

How are the hypoxia selective drugs activated

A

Reduction (normal cells don’t do a lot of reduction as they’re oxygenated)

74
Q

What is roscovitine

A

Cyclin dependent kinase inhibitor being investigated for NSCLC

75
Q

5 new targets in cancer chemotherapy

A

1) potentiation of DNA-damaging therapies
2) exploitation of tumour physiology
3) inhibition of angiogenesis
4) interference with signalling/cell cycle control
5) interference with management of DNA in tumour cell

76
Q

Two ways you can interfere in the management of DNA in newer cancer therapies

A

Inhibit telomerase activity by binding to G-quadruplex

Inhibition of tanyrase-1 preventing telomerase from binding to telomere

Oncology (9 decks)

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