Antimetabolites - Antifolate

There drugs inhibit crucial enzymes involved in nucleotide synthesis. This includes the following drugs

• Methotrexate
• Pemetrexed
• Raltitrexed

• Dihydrofolate reductase is the enzyme that reduces folic acid this results in compounds which are vital to the production of nucleotides for DNA or RNA.
• Methotrexate inhibits dihydrofolate reductase.
• Pemetrexed inhibits thymidylate transferase.
• Raltitrexed inhibits thymidylate synthase inhibitor.
• Inhibition of these enzymes leads to a lack of nucleotides and incomplete DNA or RNA synthesis and thus cell replication stops.

• Childhood acute lymphoblastic leukaemia - used for maintenance therapy and also intrathecally for prophylaxis and established disease (methotrexate)
• Choriocarcinoma (methotrexate)
• Non-Hodgkins lymphoma (methotrexate)
• Solid tumours e.g. breast cancer (methotrexate)
• Rheumatoid arthritis (methotrexate)¹
• Uncontrolled Psoriasis unresponsive to other treatments (methotrexate)²
• Unresectable malignant pleural mesothelioma with cisplatin (pemetrexed)^3,4
• Locally advanced or metastatic non-small cell lung cancer (pemetrexed)³
• Advanced colorectal cancer (NICE guidance - raltitrexed).^5,6

• Monitor full blood count, urinalysis, renal and liver function tests every 2-3 months.² Monitoring of plasma levels of methotrexate is recommended if high doses used.
• Pemetrexed requires prophylactic folic acid and vitamin B12 supplementation.

• Significant renal impairment as excreted in urine
• Severe hepatic impairment
• Avoid if presence of significant pleural or peritoneal fluid as can accumulate in these collections
• Pregnancy
• Breast feeding.

• Antifolate effect enhanced by: nitrous oxide, sulfamethoxazole, trimethoprim
• Excretion impaired by: NSAIDs (but can be used with care in rheumatoid arthritis), aspirin, ciprofloxacin, penicillins, probenicid, omeprazole
• Reduced absorption by: neomycin
• Increased risk of haematological toxicity by corticosteroids
• Pulmonary toxicity of methotrexate enhanced by cisplatin.²

• Common side effects: mucositis and bone marrow suppression. Folate inhibition is the cause of mucositis and myelosuppression. This can be counteracted by the use of folate supplements in the form of folinic acid (calcium folinate or calcium levofolinate).
• Gastrointestinal side effects (marked with raltitrexed).
• Rare side effects: pneumonitis (methotrexate), skin rashes (pemetrexed).