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They inhibit the synthesis of nucleic acids, the first necessary step for any cell multiplication. These drugs can be divided into two sub-classes:

• inhibitors of necessary enzymes, of which methotrexate is the prototype,
• lure drugs

A third class of drugs can also be considered, represented solely by L-Asparaginase which depletes circulating L-asparagine, thus depriving the cancer cells.

Antifolic drugs

Several antifolic drugs are now available, of which methotrexate is the prototype.

Methotrexate

It inhibits the folinic acid synthesis necessary for nucleic basis synthesis (uridine and thymidine), by combining with dihydrofolatereductase.

Diagram of the action of methotexate: as an inhibitor of dihydrofolatereductase, it prevents the activity of thymidilate synthetase necessary for the incorporation of nucleotide dTMP into DNA. The massive supply of folinic acid reverses its action and the combination enables more powerful chemotherapy.

Methotrexate can be used:

• either at standard doses, alone (30 to 50 mg/m²)

• or at very high dose, which can approach several grams, with the consecutive administration of its antidote, folinic acid.

This technique requires the use of repeated serum measurements of Methotrexate.

The activity of Methotrexate varies considerably depending on the dose (see page with detailed description of this product ).

Other antifolic drugs

An antifolic analogue of methotrexate now exists: raltitrexed, (Tomudex ™) the major indication of wich is the colon tumour.

Another drug whose indications are currently under exploration is pemetrexed (Alimta™) currently indicated in mesotheliomas..