The antimetabolites include three very commonly used drugs; methotrexate, 5-fluorouracil and gemcitabine. Folinic acid is used to enhance (5-FU) or oppose (methotrexate) the effects.


Methotrexate competes with folic acid and is an antagonist for the enzymes induced by folic acid. Folic acid normally supports the production of thymidine and purines, important DNA precursors, and is constantly regenerated in the cell. Inhibition of this process leads to an inability to produce the DNA precursors which is a cytotoxic effect in rapidly dividing cells.
Methotrexate is frequently used for the haematological malignancies or for leptomeningeal spread of malignancy. It can be used intrathecally for CNS disease or given systemically depending on physician preference.
Side effects include hepatotoxicity, gastrointestinal toxicity and renal toxicity.

Interaction with Radiotherapy

Radiotherapy induces cell cycle damage which needs DNA precursors for repair. This can potentially lead to synergistic effects that can cause significant normal tissue toxicity. For this reason, the two medications are not administered concurrently outside of clinical trials.


5-fluorouracil is one of the most important drugs for radiation oncologists as it is used concurrently in numerous regimens, particularly for gastrointestinal malignancies (oesophagus, stomach, pancreas, rectal, anal cancers). The molecule resembles uracil, but binds irreversibly to the enzyme thymidylate synthase leading to:

  • Impairment of production of thymidine, an important component of DNA
  • Incorporation into RNA with impairment of its function

Side effects include gastrointestinal and cardiotoxic effects. A small number of patients have a sensitivity to 5-FU and may suffer severe side effects if it is administered to them.

Interaction with Radiotherapy

As stated above, 5-FU is frequently used in combination with radiotherapy where it exhibits a radiosensitising effect. This is due to the impairment of DNA synthesis, particularly during S-phase (normally radioresistant). This occurs in both normal and malignant cells and therefore co-administration increases normal tissue toxicity, although not to the same extent as methotrexate.


Gemcitabine has similar basic properties to 5-FU, in that it is a precursor to a nucleotide that has a molecule replaced with flourine; instead of uracil the molecule is deoxycytidine (C). Similarly to 5-FU, gemcitabine appears to be a similar molecule to deoxycytidine and is incorporated into DNA, preventing action of DNA polymerase.

Side Effects

Pancytopenia, nausea/vomiting, fever/rash are most common.

Interaction with Radiotherapy

Gemcitabine is a very potent sensitiser of radiotherapy treatment with a synergistic effect. The effect is so potent that gemcitabine is rarely used in combination with radiotherapy except at low doses. More commonly, 5-fluorouracil is employed.

Folinic Acid (Leucovorin)

This medication is used in combination with 5-fluorouracil for cancers of the stomach and large bowel, where it potentiates the effect of 5-fluorouracil by stabilising its binding with thymidylate synthetase. In contrast, it actively inhibits the actions of methotrexate and is often used as a 'rescue dose' after administration of methotrexate to prevent the death of normal cells.