ANTIMETABOLITES 

Antimetabolites are a type of chemotherapy drug that work by interfering with the DNA replication process in cancer cells. They mimic the structure of essential molecules that cancer cells need to replicate their genetic information and prevent them from creating the enzymes they need to divide. 

These compounds are known as Antimetabolites because they inhibits the metabolic conversion of certain Chemicals (i.e. Folic Acid) to compounds which are essential for synthesis of DNA (Replication). 

Classified Into 3 Types:

(A) Folate Antagonist: (Methotrexate)

MOA: 

• Inhibition of Dihydrofolate Reductase (DHFR): The majority of antifolates work by inhibiting DHFR, an enzyme that reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is a necessary component in the synthesis of nucleotide precursors, so when DHFR is inhibited, it leads to a deficiency in the nucleotide precursors, thus inhibiting DNA synthesis.

(B) Pyrimidine Antagonist: (5-Flurouracil) 

MOA

• 5-FU is converted to its active metabolites, fluorodeoxyuridine monophosphate (FdUMP)
• FdUMP forms a stable ternary complex with thymidylate synthase (TS) blocking the enzyme's ability to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). 
• This leads to a depletion of dTMP, which is a building block of DNA.

ADR of 5FU: 

1. Diarrhoea
2. Heartburn 
3. Rash 
4. Nausea, vomiting 
5. Weakness 
6. Fever 
7. Abdominal cramps 

(C) Purine Antagonist: (6-marcaptopurine) 

MOA 

• 6-MP is converted to its active metabolite, 6-thioguanine nucleotide (6TGN)
• 6TGN inhibits PRPP aminotransferase, an enzyme involved in the synthesis of purine nucleotides, which are the building blocks of DNA and RNA. 
• This can lead to a depletion of purine nucleotides and a block in DNA and RNA synthesis.

USES of ANTIMETABOLITES 

1. Leukemia: Antimetabolites are commonly used to treat different types of leukemia
2. Breast Cancer: These drugs are used in the treatment of breast cancer
3. Ovarian Cancer: Antimetabolites are used to treat ovarian cancer
4. Intestinal Cancer: These drugs are also used in the treatment of cancers of the intestinal tract
5. Lung Cancer: Antimetabolites are used to treat lung cancers