Anti-metabolites

Question 2

What are antimetabolites?

Answer 2

Antimetabolites are drugs that kill cancer cells by inhibiting critical cellular processes, usually through enzyme inhibition.

Question 3

How do antimetabolites work?

Answer 3

They mimic or inhibit natural metabolites, mainly used to inhibit DNA synthesis, especially in rapidly dividing cancer cells.

Question 4

What is the common mechanism of antimetabolites?

Answer 4

The common mechanism is enzyme inhibition, disrupting nucleic acid biosynthesis.

Question 5

What major cancer hallmark do antimetabolites target?

Answer 5

Antimetabolites target the hallmark of limitless replicative potential.

Question 6

What are the 4 main classes of antimetabolite drugs?

Answer 6

1. Folate Antagonists
2. Pyrimidine Antagonists
3. Purine Antagonists
4. Sugar-Modified Nucleosides

Question 7

What are examples of Folate Antagonists?

Answer 7

Methotrexate, Pemetrexed, Raltitrexed

Question 8

What are examples of Pyrimidine Antagonists?

Answer 8

5-FU, FdURD, Azacytidine

Question 9

What are examples of Purine Antagonists?

Answer 9

6-MP, Thioguanine

Question 10

What are examples of Sugar-Modified Nucleosides?

Answer 10

Cytarabine, Gemcitabine, Fludarabine

Question 11

What is folic acid?

Answer 11

Folic acid is also known as vitamin B9 and is a B vitamin.

Question 12

How is folic acid utilized by the body?

Answer 12

Folic acid is converted into folate by the body.

Question 13

What is the role of folic acid in pregnancy?

Answer 13

Folic acid is used as a dietary supplement and is useful in pregnancy.

Question 14

Why does the body require folate?

Answer 14

Folate is required for the synthesis of DNA and RNA and to metabolize amino acids.

Question 15

Describe the folate cycle

Answer 15

1) SHMT combines TNF with a carbon unit from L-serine
Produces 5,10-CH2-TNF
L-serine is converted to glycine in the process
2) Transfer of one carbon unit
The CH2 from 5,10-CH2-TNF is repositioned
This group is the one-carbon donor used later in nucleotide synthesis
3) TS uses 5,10,CH2-THF to convert dUMP -> dTMP by adding a methyl group (CH2->CH3)
4) During the above reaction - dUMP is the substrate
5) DHFR reduces DHF back to THF using NADPH as the reducing agent. This regenerates active folate for another cycle

Question 16

Define the mode of action of methotrexate

Answer 16

Mimics dihydrofolate -> inhibits DHFR
Binds to DFHR at folate-binding site

Question 17

What are the resistance mechanisms methotexate?

Answer 17

DHFR mutations - modifying the folate binding site, multi-drug resistance phenotype, causing active efflux of drug, RFC mutations, reducing uptake

Question 18

Define the mode of action is pemetrexed, raltitrexed

Answer 18

Inhibit TS
Directly binds to the 5,10-CH2-tetrahydrofolate binding site

Question 19

Define the mechanism of TS

Answer 19

dUMP forms a covalent bond with a cysteine residue in the active site of the TS enzyme
This occurs via Michael Addition, where the sulfur nucleophile attacks the electron deficient double bond in dUMP
Binary complex between dUMP and TS
Formation of tertiary complex
Nect 5,10-CH2-TNF acts as both a carbon donor (CH2) and reductant
A tertiary complex is now formed, TS-dUMP-5,10-CH2-THF
Methylene group is transferred to dUMP forming dTMP. The CH2 is reduced to CH3 during the process
dTMP is released
DNF is left behind as 5,10-CH2-THF is oxidised
TS is regenerated and ready for another cycle

Question 20

Define the mode of action of 5-FU

Answer 20

Converted to FdUMP which binds TS, blocking dTMP synthesis
Leads to thymineless death (halted DNA synthesis
Long-acting due to inability to be metabolically cleared (fluroine present)

Question 21

Mode of action of azacytidine and decitabine

Answer 21

Involves adding a CH3 to cytosine resdiues typically at CpG islands in gene promoters
Cancer cells exploit DNA methylation to silence tumour suppressor genes
They act as suicide inhibitors of DNA methyltransferases (DNMTs) - Trap DNMTs during methylation, cause DNMT degradation, result in hypomethylation of DNA
Hypomethylation -> reativation of silenced tumour suppressor genes
Targeted epigenetic therapy

Question 22

Mode of action of 6-MP a purine antagonist

Answer 22

Incorporated into DNA in place of natural guanine -> base mismatch -> strand breaks -> cell death

Question 23

Mode of action of cytarabine

Answer 23

Phosphorylated into active triphosphate forms
incorporated into DNA and RNA
Cause chain termination or inhibit polymerases
dCTP analogue -> inhibits DNA polymerase, halts DNA synthesis

Question 24

Define mode of action of gemcitabine

Answer 24

Inibitition of RR
F2dCDP inhibits RR which reduces the pool of natural deoxynucleotides
This starves the cell of DNA building blocks, halting replication
DNA incorporation
F2dCTP is incorporated into DNA in place of dCTP
Once inserted it does cause masked chain termination
The next nucleotide is added
But no further extension occurs
Leads to inhibition of DNA synthesis and apoptosis

Question 25

What is the mechanism of self-potentiation?

Answer 25

🔁 Mechanism of Self-Potentiation: Gemcitabine is phosphorylated → F₂dCDP F₂dCDP inhibits: CTP synthase (↓ CTP) Ribonucleotide reductase (↓ dCTP) dCTP normally inhibits dCK (deoxycytidine kinase) via feedback: dCK is the first enzyme that activates gemcitabine High dCTP → inhibits dCK (less gemcitabine activation) Low dCTP → activates dCK (more gemcitabine activation) Result: Gemcitabine depletes dCTP, which relieves dCK inhibition This boosts further activation of gemcitabine → positive feedback loop