Chapter 3- Threadgill Flashcards by Rachel Cornish

What is an antimetabolite?

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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The enzymes that antimetabolites inhibit are involved in what?

DNA biosynthesis

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

Serine hydroxymethyltransferase (SHMT)

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Name three enzymes in the folate cycle

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

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In the folate cycle what does dihydrofolate reductase convert?

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

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What does the enzyme thymidylate synthetase convert and with what cofactor

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

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How does methotrexate work

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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What’s often given with methotrexate to rescue normal cells

Leucovorin (folate)

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List 3 ways people can become resistant to MTX

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

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Name 4 lipophilic antifolate antimetabolites

Pyrimethamine
Methylbenzoprim
Piritrexim
Nolatrexed

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What is nolatrexed and what is it licensed to treat

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

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What are pemetrexed and raltitrexed?

Antifolate antimetabolites they are inhibitors of thymidylate synthetase

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How does 5-FU and FdURD work

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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Is 5-FU a prodrug?

Yes

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Name three antimetabolites that are classed as pyrimidine antagonists

5-FU
FdURD
Azacytidine

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How does azacytidine work

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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Name 3 purine antagonists

6-mercaptipurine
Thioguanine
Tiazofurin

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

Tiazofurin

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TAD is from what drug and how does it inhibit biosynthesis

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

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How does 6-mercaptopurine and 6-thioguanine work?

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

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

Guanosine-5’-monophosphate (GMP)

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

6-mercaptopurine

Inhibits adenylo-succinate synthetase

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TAD from what drug inhibits what enzyme

Tiazofurin

Inhibits IMP dehydrogenase by binding at NAD+ binding site

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

IMP dehydrogenase through binding at the purine binding site

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6-mercaptopurine looks like what?

Hypoxanthine

Thioguanine looks like what

Guanine

Explain the activation of purine analogues

6-MT -> Thio-IMP 6-thioguanine -> thio-GMP (Through enzyme HPRT) Thio-GMP --> thio-GTP (TG-RNA) Thio-GMP --> thio-dGTP (TG-DNA)

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

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

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

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

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

Adenylo-succinate synthetase IMP dehydrogenase

Pathways to make GMP

IMP-> AMP | IMP-> XMP -> GMP

Name three antimetabolites that are sugar-modified nucleosides

Cytarabine (Ara-C) Fludarabine Gemcitabine

What is cytarabine and how does it work

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

How does fludarabine work and what is it

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

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

F2dC F2dCMP F2dCDP F2dCTP

List the enzymes in order of involvement in the gemcitabine mechanism

Deoxycytidine kinase UMP/CMP kinase NDP kinase

F2dCDP inhibits what two enzymes

CTP synthase | Ribonucleotide reductase

What is the role of microtubules

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

Name the 5 steps of mitosis (M phase)

``` Prophase Prometaphase Metaphase Anaphase Telophase ```

What happens in prophase

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

What happens in prometaphase

Microtubules attach to the centromeres of the chromosomes

What happens in metaphase

Chromosomes align along metaphase plate

What happens in anaphase

Centromeres and chromosomes separate, spindle poles move further apart

What happens in telophase

Nuclear envelope assembles

What's a kinetochore

Bit of microtubule that attaches to chromosome

What's the spindle pole

Position to which the chromosomes are to be pulled

What's the kinetochore microtubule

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

What's the astral microtubules

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

What is a microtubule made up of?

Tubulin dimers

What are tubulin dimers made up of

One alpha and one beta subunit

Microtubules are in what with individual tubulin dimers

Dynamic equilibrium

How do mitotic spindle poisons principally work

Interfere with the dynamic equilibrium between microtubules and individual tubulin dimers

Name four vinca alkaloids

Vincristine Vinblastine Vinorelbine Vindesine

Name two taxols

Paclitaxel (taxol) | Docetaxel (taxotere)

How does taxol and its derivatives work

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

Problems with taxol and it's derivatives

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

Which is better: paclitaxel or docetaxel

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

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

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

How do colchicine like drugs work

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

Name two colchicine like drugs

Colchicine | Combretastatin A-4

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

MGMT

Name two drugs that inhibit the repair enzyme MGMT

O6-benzylguanine | Patrin

PARP-1 is essential for what types of repair

Nucleotide excision repair | Single strand break repair

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

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

What is XL844?

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

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

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

Example drug that inhibits DNA dependent protein kinase

NU7441

List four was tumours have poor vascular structure

Disorganised network Vessel walls not well formed Leaky High interstitial pressure

Three zones of a tumour

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

Why are hypoxic tissues less sensitive to radiotherapy

Radiotherapy requires oxygen

Name two radiosensitising drugs

Electron-affinic radiosensitisers: 1) pimonidazole 2) etanidazole

Name 4 hypoxia-selective drugs

Nitroimidazoles Mitomycin C Tirapazamine AQ4N

How are the hypoxia selective drugs activated

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

What is roscovitine

Cyclin dependent kinase inhibitor being investigated for NSCLC

5 new targets in cancer chemotherapy

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

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

Inhibit telomerase activity by binding to G-quadruplex Inhibition of tanyrase-1 preventing telomerase from binding to telomere