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Cancer - All topics > MDT - Antimetabolites > Flashcards

MDT - Antimetabolites Flashcards

1
Q

What is an antimetabolite?

A

Kill cells by inhibiting cellular process which is critical. Normally some critical enzyme in the growth and replication of cells (DNA biosynthesis).

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2
Q

How many groups of antimetabolite drugs are there?

A 
Four. 
Folate antagonists. 
Pyrimidine antagonists. 
Purine antagonists. 
Sugar-modified nucleosides.
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3
Q

What are some examples of folate antagonists?

A

Methotrexate, non-classical lipophillic antifolates, pemetrexed, raltitrexed.

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4
Q

Are folate antagonists really antagonists?

A

No they just inhibit enzymes, not true receptor antagonists.

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5
Q

What are some examples of pyrimidine antagonists?

A

5-Fluorouracil (5-FU), fluorodeoxyuridine (fdURD), azacytidine.

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6
Q

Pemetrexed

A

Folate antagonist

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7
Q

What is the folate cycle?

A

L-serine –> Thymidine

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8
Q

Thymidylate synthase (TS) ThyA is an enzyme crucial for

A

DNA synthesis

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9
Q

TS catalyses the conversion of ______ and _______ into ______ and ______ via _________

A

TS catalyses the conversion of dUMP and mTHF into dTMP and DHF via reductive methylation.

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10
Q

What is “thymineless death”?

A

The reaction catalysed by TS is a pivotal step in the de novo biosynthesis of dTTP (one of the four building blocks of DNA). Inhibition of TS, in the absence of preformed thymidine, blocks DNA synthesis -> cell death.

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11
Q

The mechanism which TS catalyses to form dTMP and DHF from dUMP and mTHF

A

Reductive methylation

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12
Q

What is the most widely used agent for targeting overexpression of TS?

A

5-FU - based on the observation that uracil may be preferentally used in DNA synthesis in tumours compared to normal cells.

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13
Q

Why is 5-FU effective at treatment of tumours?

A

5-FU is anablolised to a nucleotide analog of dUMP (FdUMP), which is a tight binding inhibitor of TS.
The reaction stops as the fluorine substituent fails to dissociate from the pyrimidine ring, resulting in inactivation of the enzyme.

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14
Q

Why is 5-FU not an optimal drug? [3]

A

It is inefficiently converted to FdUMP.

Part of it catabolised to toxic metabolites.

Also tumours can exhibit acquired or intrinsic resistance to FUra.

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15
Q

What is an important factor reducing the effectiveness of FdUMP as TS inhibitor?

A

Metabolic resistance, a phenomenon consisting of the protection of enzyme against drugs by accumulation of substrate to the level sufficient to compete efficiently with the inhibitor, leading to full activity of the metabolic pathway involving the target enzmye.

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16
Q

Why did researchers focus on analogues of the folate cofactor of TS? What did this lead to?

A

The metabolic resistance to FdUMP, this led to the development of inhibitors of the folate cofactor - the antifolates.

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17
Q

What is Raltitrexed?

A

Direct and specific inhibitor of TS.

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18
Q

On what was Raltitrexed modelled?

A

CB3717

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19
Q

How does the structure of Raltitrexed differ from that of CB3717?

A

CH2-C~CH group and benzene ring replaced with methyl group and thiophene ring.

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20
Q

What is metabolic resistance?

A

Metabolic resistance, a phenomenon consisting of the protection of enzyme against drugs by accumulation of substrate to the level sufficient to compete efficiently with the inhibitor, leading to full activity of the metabolic pathway involving the target enzmye.

RE: FdUMP effectiveness.

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21
Q

What was the rational behind the changes to the structure of CB3717 to make Raltitrexed

A

The CH2-C~CH group and benzene ring replaced with methyl group and thiophene ring was done to create a more water soluble, non-nephrotoxic and more potent drug.

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22
Q

Raltitrexed is an analogue of

A

mTHF and therefore cannot be incorporated into DNA.

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23
Q

How is Raltitrexed transported into the cell?

A

Reduced Folate Carrier (RFC)

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24
Q

What happens to Raltitrexed once it is in the cell?

A

It becomes polyglutamated via FPGS, this makes it 100-fold more inhibitory active and retains within cells for a much longer time.

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25
Q

The ability of Raltitrexed to compete with the mTHF cofactor at the enzyme site does not depend on what?

A

Does not depend on the formation of a covalent bond between the catalytic cysteine and the pyrimidine ring o the dUMP substrate - further drug study came from this.

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26
Q

Raltitrexed was first approved for treatment of

A

mCRC, metastatic colorectal cancer.

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27
Q

Who now uses Raltitrexed?

A

Only those who are intolerant to other therapies, such as 5-FU.

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28
Q

What causes Raltitrexed to become 100-fold more inhibitory?

A

Polyglutaminaton via FPGS.

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29
Q

What are pemetrexed and raltitrexed?

A

Antifolate metabolites

Inhibit TS

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30
Q

What is cytarabine?

How does it work?

A

Modified sugar nucleoside.

Converted into triphosphate inhibits DNA polymerase as it is an analogue of dCTP.

31
Q

A sugar modified nucleoside that is converted to a triphosphate and inhibits DNA polymerase as it is an analogue of dCTP

A

Cytarabine (see also fludarabine)

32
Q

_________ is a sugar modified ___________ that is converted to a __________ and inhibits ___ ____________ because it is an analogue of ________

A

Cytarabine is a sugar modified nucleoside that is converted to a triphosphate and inhibits DNA polymerase as it is an analogue of dCTP

33
Q

What is fludarabine?

How does it work?

A

Fludarabine (Fludara ®) is a chemotherapy drug used to treat chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and some types of non-Hodgkin lymphoma.

Sugar modified nucleoside that is converted to a triphosphate and inhibits DNA polyermas as it is an analogue of dCTP.

34
Q

What does 6-mercaptopurine look like?

A

Hypoxanthine.

Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids, where it is present in the anticodon of tRNA.

35
Q

What are 4 lipophillic antifolate metabolites? why are they better?

A

They do not need reduced folate carriers.

Primethamime
Methylbenzoprim
Piritrexim
Nolatrexed

36
Q

What are 3 antimetabolites that are classed as pyrimidine antagonists?

A

5-FU
FdURD
Azacytidine - chemical analogue of cytidine a nucleoside in DNA.

37
Q

What are three antimetabolites that are sugar-modified nucleosides?

A

Cytarabine (ARa-C)
Fludarabine
Gemcitabine

Converted to triphosphates and inhibit DNA as analogues for dCTP.

38
Q

What are pemetrexed and ralititrexed?

A

Antifoalte metabolites that inhibit TS

39
Q

6-mercaptopurine inhibits which enzyme?

A

6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called Phosphoribosyl pyrophosphate amidotransferase (PRPP Amidotransferase). PRPP Amidotransferase is the rate limiting enzyme of purine synthesis. This alters the synthesis and function of RNA and DNA.

(The conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP).)

Thio-IMP is a metabolite of this.

40
Q

What is nolatrexed? What is it licensed to treat?

How does it work?

A

Nolatrexed = lipophillic inhibitor of folate cycle.
Licensed: liver cancer.
Works: Inhibits DHF and TS

41
Q

What are the order of products in the gemcitabine (f2dC) mechanism?

A 
F2dC
>dCK<
F2dCMP
>UMP/CMP kinase<
F2dCDP
>NDP kinase<
F2dCTP

F2dCDP inhibits both CTP synthase and the next enzyme in the step ribonucleotide reducatase. Preventing formation of CTP and then dCTP.

Also, dCTP is a feedback inhibitor of the enzyme dCK, which turns F2dC into F2dCMP. Hence, depletion of dCTP activates dCK.

Activation of dCK increases the formation of F2dCMP from gemcitabine.

42
Q

What is the relevance of the sulphur (instead of oxygen) in the structures of 6-MP and 6-TG?

A

Unable to form hydrogen bonds as it is not as electronegative as oxygen.

43
Q

Both 6-MP and 6-TG bind where?

A

Purine binding site.

44
Q

How does 6-MP inhibit DNA synthesis?

A

6-MP, used in the treatment of leukeamia, is an example of an allosteric inhibitor. It inhibits the first enzyme involved in the synthesis of purines and blocks their synthesis.

45
Q

How does azacytidine work?

A

Pyrimidine antagonist.

Mimics cytidine, prodrug which is phosphorylated to azacytidine triphosphate and incorporated into RNA making it unstable and prone to decomposition.

46
Q

What are the four main groups of antimetabolite drugs?

What are some examples?

A

Folate antagonists: methotrexate, non-classical lipophillic antifolates, pemetrexed, raltitrexed.

Pyrimidine antagonists: 5-FU, Fluorodeoxyuridine (FdURD) and azacytidine.

Purine antagonists: 6-Mercaptopurine, thioguanine, tiazofurin.

Sugar-modified nucleosides: Cytabarine, fludarabine, gemcitibine.

47
Q

F2dCDP, the product of Gemcitabine, inhibits which two enzymes?

What is the outcome of this?

A

F2dCDP inhibits both CTP synthase and ribonucleotide reductase.

CTP synthase converts UTP into CTP.

Ribonucleotide reductase converts CTP into dCTP.

Gemicitabine self-potentiates: dCTP normally inhibits the activation of dCK, the first enzyme in the activation pathway of Gemcitabine that ultimately results in F2dCTP.

48
Q

What is the role of microtubules?

A

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

49
Q

What are three purine antagonists?

A

6-MP
Thioguanine
Tiazofurin

50
Q

How are the purine antagonists activated?

A

6-MP —HPRT—> Thio-IMP —> Thio GMP.

Thio-GMP —–> Thio-GTP ——-> RNA

Thio-GMP ——> Thio-dGTP —-> DNA

6-TG —-HPRT—> Thio-GMP ——> As above.

51
Q

How is GMP created?

At which stage in this process do the following work:

Thio-IMP (2 places)
TAD (from where?)
Thio-GMP

A

IMP is converted into AMP via the enzyme Adenylo-succinate synthetase.

Thio-IMP inhibits the Adenylo-succinate synthetase enzyme preventing this conversion. (1 place of action for Thio-IMP).

IMP is converted into GMP via IMP dehydrogenase into XMP and then via XMP-Gln amino-transferase into GMP.

Thio-IMP (second place of action) inhibits the enzyme IMP dehydrogenase by binding at the purine binding site. (Thio-GMP, from 6-TG, also works at this site).

TAD, from the now withdrawn drug tiazofurin, also inhibits the IMP dehydrogenase enzyme. It does this by binding at the NAD+ binding site.

52
Q

What are the five stages of mitosis?

PPMAT

A 
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
53
Q

What occurs during prophase? (3)

A
  1. Chromosomal material condenses to form a compact mitotic chromosome
  2. Cytoskeleton is disassembled and mitotic spindles assembled.
  3. Nuclear envelope disperses
54
Q

What happens in prometaphase?

A

The microtubules attach to the centromeres of the chromosomes.

55
Q

What happens in metaphase?

A

Chromosomes align along the metaphase plate.

56
Q

What happens in anaphase?

A

Centromeres and chromosomes separate, spindle poles move further apart.

57
Q

What happens in telophase?

A

Nuclear envelope assembles

58
Q

What is a kinetochore?

A

Bit of microtubule that attaches to chromosome.

59
Q

What is the spindle pole?

A

The position to which the chromosomes are to be pulled.

60
Q

What is the kinetochore microtubule?

A

The bit that anchors the chromosomes to the centre of the spindle.

61
Q

What is the astral microtubule?

A

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

62
Q

What is a microtubule made up of?

A

Tubulin dimers

63
Q

What are tubulin dimers made up of?

A

One alpha and one beta subunit.

64
Q

Microtubules and individual tubulin dimers have what type of relationship?

A

They are in a dynamic equilibrium: Le Chateliers principle.

Mitotic spindle poisons ork principaly by interfering with the dynamic equilibrium between microtubules and individual tubulin dimers.

65
Q

How do mitotic spindle poisons work primarily?

A

They interfere with the dynamic equilibrium that exists between microtubules and individual tubulin dimers.

66
Q

What are 4 vinca alkaloids?

A

VinCRISTINE
VinBLASTINE
VinORELBINE
VinDESINE

67
Q

Name 2 taxols

A

Paclitaxel (taxol)

Docetaxol (taxotere)

68
Q

How does taxol and its derivatives work? [4]

A
  1. Taxols bind to taxol-binding sites on the inside surface of the microtubule, preventing disassembly.
  2. Inappropriate microtububles remain.
  3. Concentrations of free tubulin dimers decreases.
  4. The low concentration of free tubulin dimers means that new microtubules cannot be assembled.
69
Q

What are the problems with taxol and its derivatives? [3]

A
  1. Very insoluble so have to be given IV.
  2. Hypersensitivity reactions due to the excipients it is formulated with.
  3. There is a correlation between increased solubility and decreased activity.
70
Q

The better taxol is:

A

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

Paclitaxel: mammary carcinoma, ovarian carcinoma.

Docetaxel: Prostate, mammary, ovarian and lung carcinoma.

71
Q

Where does taxol come from and why is this a problem?

A 
Pacific yew (Taxus brevifolia).
It takes 3 trees to make one course of treatment for a patient.
72
Q

How do the colchicine drugs work?

A
  1. Bind to colchicine binding sites on beta-tubulin subunits.
  2. This disfavours assembly of protofilaments.
  3. Also disfavours the DISASSEMBLY of inappropriate microtubules.

Two colchicine like drugs: Colchicine (gout)
Combrestatin a-4. (CT for cancer)

73
Q

What is Combretastatin A-4?

A

Colchicine like drug in clinical trials for treatment of cancer.

Cancer - All topics (32 decks)

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