Exploring the Pharmacology of Antimetabolite Drugs

• Antimetabolite drugs interfere with the enzymes required for DNA synthesis. The common indications for these drugs are bacterial infections, viral infections, arthritis, and cancers. 
• They alter normal cell metabolism by replacing or inhibiting the enzymes required for DNA and RNA synthesis. 
• Here we will review the basic pharmacological actions of these drugs as anticancer agents. 

Antimetabolite drugs interfere with the enzymes required for DNA synthesis. The common indications for these drugs are bacterial infections, viral infections, arthritis, and cancers. 

Here we will review the basic pharmacological actions of these drugs as anticancer agents. 

Antimetabolites are the first discovered effective chemotherapeutic agents against cancer. They alter normal cell metabolism by replacing or inhibiting the enzymes required for DNA and RNA synthesis. These drugs resemble the molecules required for nucleic acid synthesis and usually cause cell death in the S phase. 

Classes and Indications for Antimetabolite Drugs

Folate Antagonist

• Methotrexate: breast cancer, skin cancer, head and neck cancer, and lung cancer. Also, for psoriasis and rheumatoid arthritis. 
• Pemetrexed: non-small cell lung cancer, cervical cancer, ovarian cancer, and malignant pleural mesothelioma 
• Raltitrexed: colorectal cancer 

Pyrimidine Pathway Antagonists

• Azacitidine: myelodysplastic syndromes 
• Capecitabine: breast cancer 
• Cytarabine: leukaemia alone as well as associated with meningitis. 
• Decitabine: myelodysplastic syndrome 
• Gemcitabine: pancreatic cancer, lung cancer, ovarian cancer, and breast cancer 
• Fluorouracil: colorectal cancer, breast cancer, stomach cancer, and pancreatic cancer 
• Tegafur: metastatic colorectal cancer 

Purine Pathway Antagonists

• Cladribine: non-Hodgkin’s lymphoma, hairy cell leukaemia, chronic lymphocytic leukaemia, and relapsing multiple sclerosis. 
• Clofarabine: acute lymphoblastic leukaemia 
• Fludarabine: B-cell chronic lymphocytic leukaemia 
• Mercaptopurine: acute lymphoblastic and lymphocytic leukaemia 
• Nelarabine: T cell acute lymphoblastic leukaemia and T cell lymphoblastic lymphoma 
• Pentostatin: hairy cell leukaemia 
• Thioguanine: leukaemia 

Mechanism of Action for Antimetabolite Drugs

Antimetabolite drugs resemble the natural substrates required for DNA and RNA synthesis. However, at the same time, they are different enough to cause cell destruction. They target both, the healthy and cancerous cells, but they show greater effects on cancer cells. That could be because of their fast replication rate. Antimetabolites kill cancerous cells by disrupting their nucleic acid synthesis. 

Pyrimidine pathway antagonists work by interfering with uracil and cytosine, the pyrimidine bases. These bases are necessary for DNA synthesis. Since pyrimidine antagonists resemble the nucleotide bases, they get attached to the DNA. Then they are converted into metabolites that inhibit the activity of the enzyme thymidylate synthetase. Normally, this enzyme converts uracil to thymidine by adding a methyl group on 5th carbon and let the cell cycle proceed.  

Inhibition of thymidylate synthetase causes DNA synthesis failure and cell death eventually. These drugs also target RNA by incorporating one of their metabolites into it. It causes faulty RNA translation, inhibiting its synthesis and blocking all its different forms. These combined actions on DNA and RNA synthesis cause damage to cancerous cells. 

Purine pathway antagonists target adenine and guanine bases. They stop nucleotide synthesis by decreasing the purine base production or incorporating themselves into the DNA strands during synthesis. Hence stopping the cell growth. Since they resemble nucleotide bases, they get attached to them and convert into metabolites that inhibit the first step of purine synthesis.  

They may also block the formation of adenosine monophosphate and xanthinuric acid from inosinic acid. These drugs convert into their metabolites, and incorporate into RNA, resulting in their faulty translation and inhibition of RNA synthesis and all in their different forms. 

Resistance to Antimetabolite Drugs

Resistance to these drugs can occur due to genetic mutation. Folate antagonists work by targeting an enzyme dihydrofolate reductase (DHFR), an enzyme necessary for folic acid production. Folic acid is a necessary compound for nucleotide synthesis, so its inhibition eventually stops nucleotide formation.  

Normally, in nucleotide synthesis, DHFR converts to dihydrofolate, reduces to tetrahydrofolate (TDHF), acts as a carbon carrier, and donates methyl groups to the end target molecules. This process takes place via enzymatic action of thymidine synthetase. Since folate antagonists use DHFR, the nucleotide synthesis is stopped.  

Drug resistance with methotrexate can occur due to: 

• Decreased drug transport into the cells 
• Genetic mutation (this alters the enzyme binding constants or causes an increase in the enzyme DHFR within the cell) 

Side Effects of Antimetabolite Drugs

• Mucositis 
• Stomatitis 
• Alopecia 
• Skin diseases 
• Anaemia 
• Thrombocytopenia 
• Opportunistic infections 
• Myelosuppression
  

Some other side effects include: 

• Pentostatin has a black box warning of excessive sedation, seizures, and weakness. It may also cause renal impairment, lung problems, and liver toxicity. 
• Thioguanine may cause fluid retention that can lead to ascites. It can also cause veno-occlusive liver disease, hepatomegaly, portal vein hypertension, and jaundice. 
• Nelarabine can cause demyelination of neurons, seizures, severe somnolence, ascending peripheral neuropathies, altered mental state, abnormal gait, pleural effusion, and cough. 
• Fludarabine can cause severe CNS toxicity leading to blindness and coma. It can also cause fatal autoimmune hemolytic anemia, Evan’s syndrome, and acquired haemophilia. 
• Methotrexate has a black box warning of diarrhea and ulcerative stomatitis 

Clinical Considerations

• Fludarabine and pentostatin should never be given in combination because they can cause severe lung problems. Pentostatin should also be avoided in patients with prior lung diseases because it could be fatal for them. 
• Patients administered with fludarabine should be monitored closely for hemolysis. 
• Treatment of malignancy with cladribine may, in turn, increase the malignancy risk. It should be avoided in patients with a prior history of malignancy or at risk for it. 
• Cytarabine is administered intrathecally as liposomal cytarabine. It can cause chemical arachnoiditis, which can be fatal if left untreated. However, dexamethasone can help in reducing the symptoms. 
• Patients receiving capecitabine and coumarin derivatives, concomitantly, should be monitored closely for blood coagulation and INR because their combination can increase the risk of bleeding.
• Tumour lysis syndrome can occur with methotrexate. It should be managed symptomatically. Otherwise, it would be fatal. 

Here, we complete the basic pharmacological review of antimetabolite anticancer drugs. 

Read More