Antimetabolites

Antimetabolite drugs interfere with the synthesis of the building blocks of DNA (purine and pyrimidine bases or their corresponding nucleosides), disrupting DNA (and for some drugs RNA) synthesis and replication. Most of these drugs are structural analogues of the endogenous molecules or folate cofactors crucial for purine and pyrimidine biosynthesis. Antimetabolite class drugs principally target the de novo nucleotide synthetic pathways crucial for supplying the large nucleotide pools required by highly proliferating cancer cells. Antimetabolite drugs can be categorised into three primary subgroups:

1. folic acid antagonists
2. purine analogues
3. pyrimidine analogues.

1. Folic acid antagonists

Methotrexate is both a chemotherapeutic agent and a general immunosuppressant for systemic inflammatory diseases such as rheumatoid arthritis and psoriasis. Often used to counteract systemic inflammation in rheumatic conditions, such drugs are known as disease-modifying antirheumatic drugs (DMARDs), with methotrexate emerging as a first-line DMARD.

Methotrexate inhibits dihydrofolate reductase (DHFR), the primary enzyme responsible for converting folic acid to its more physiologically active reduced form folate-  an essential step in DNA synthesis. Consequently methotrexate treatment results in a build-up of inactive folates. Despite resembling folate, methotrexate can induce a range of toxicities, including myelosuppression (dose-limiting), mucositis, hepatotoxicity, nephrotoxicity and neurotoxicity. To mitigate nephrotoxicity, vigilantly maintaining hydration and alkalinising urine (achieving pH >7) are recommended. Additionally, patients taking methotrexate should avoid concomitant use of other nephrotoxic drugs and those that may interact with methotrexate. For example, certain weak acids like non-steroidal anti-inflammatory drugs (NSAIDs) and penicillin compounds may precipitate methotrexate. The fixed-dose antibacterial medication trimethoprim/sulfamethoxazole may compete for reabsorption in renal tubules, and proton pump inhibitors such as omeprazole may inhibit the clearance of methotrexate, thereby exacerbating side effects. The risk of methotrexate-induced adverse effects escalates with dosage. Therefore, in the case of high-dose methotrexate administration (>1000 mg/m²), supplementation with leucovorin (folinic acid; a reduced form of folate) is advised. This approach, known as a 'leucovorin rescue' supplies essential folate in a usable form to combat the myelosuppression and gastrointestinal toxicity observed in patients treated with high-dose methotrexate. Leucovorin counters the folate depletion caused by methotrexate, primarily benefiting the healthy (non-cancer) cells. Administered 12-24 hours post methotrexate infusion, leucovorin treatment continues until methotrexate is eliminated from the body. Alternatively, high-dose folic acid supplementation can achieve the same benefit.

It is hypothesised that cancer cells, likely exhibiting elevated active dihydrofolate reductase levels, preferentially bind methotrexate, partially sparing its impact on normal cells. As methotrexate can accumulate in the interstitial space between cells, its levels are routinely monitored. If significant accumulation transpires, glucarpidase (a recombinant bacterial enzyme that breaks down methotrexate into inactive metabolites) can be administered to quickly lower heightened methotrexate levels in patients suffering from severe toxicity due to the drug.

2. Purine analogues

6-mercaptopurine (6-MP) is an active metabolite derived from the prodrug, azathioprine. It functions by incorporating into DNA in place of the natural purine bases, thereby interfering with DNA synthesis and leading to miscoding in both DNA and RNA. Consequently, DNA replication is impaired and the proliferation of cancer cells is hindered. 6-MP is primarily indicated for acute lymphoid leukaemia (ALL). However, the use of 6-MP can result in common adverse reactions such as myelosuppression (suppression of bone marrow function leading to reduced blood cell production), mucositis (inflammation of the mucous membranes), nausea/vomiting and hepatotoxicity (liver toxicity). Furthermore, it is important to be aware of several significant drug-drug interactions that may arise from clinical use. For instance, co-administration of allopurinol can elevate the concentration of 6-MP, potentially increasing its toxicity.

3. Pyrimidine analogues

5-fluorouracil (5-FU) is the most commonly used pyrimidine analogue in clinical practice. It acts as an analogue of pyrimidines, specifically thymine and cytosine, and exterts its mechanism of action by inhibiting the activity of thymidylate synthase (TYMS). TYMS plays a crucial role in the rate-limiting step of thymidine generation, which is essential for DNA synthesis and cellular proliferation. Upon administration 5-FU is metabolised into its active form, 5-fluorouracil triphosphate, which is incorporated into RNA.

The primary therapeutic use of 5-FU is in the treatment of various cancers, including colon, pancreatic, and head and neck cancers, as well as certain haematological malignancies. However, the toxicities associated with 5-FU can vary depending on the method of administration. Bolus intravenous infusions are linked to myelosuppression, while continuous intravenous infusions can lead to mucositis, diarrhoea, and hand-foot syndrome. Other reported adverse effects include phototoxicity, cardiotoxicity, skin manifestations and rashes, alopecia, and ocular toxicity.

Folinic acid (leucovorin) is often administered in combination with 5-FU to enhance the drug's effectiveness. Leucovorin increases the stability of 5-FU's binding to thymidylate synthase, thereby augmenting its pharmacological action. This combination allows lower doses of 5-FU to be effective while attenuating some of the associated side effects. It is important to note that leucovorin is not used as a rescue medication in the same manner as it is in methotrexate regimens.

Another useful drug in the pyrimidine class is cytarabine. Originally isolated from a Caribbean sea sponge, cytarabine is now synthesised chemically. It demonstrates potent anti-cancer activity and has proven an effective medication for leukaemias and lymphomas. Cytarabine is a prodrug whose active metabolite is ara-cytosine triphosphate. This metabolite is incorporated into DNA during replication, leading to the blockage of DNA polymerase processivity. As a result chain synthesis is disrupted. Cytarabine also induces miscoding in RNA. Common adverse effects of cytarabine include myelosuppression, which involves the suppression of bone marrow function leading to reduced blood cell production. Nausea and vomiting, cerebellar toxicity (manifesting as neurologic symptoms), and conjunctivitis are also common adverse effects of cytarabine.