Méthotrexate

Indications

Cytostatique employed before in poly Chemotherapy in the treatment of many Cancer S, it is still used in first line in the treatment of the acute lymphoblastic Leucémie and others Néoplasie S, like in Prophylaxie in the cerebral Tumeur S.

It recently was used and recorded in the treatment of autoimmune diseases, of which the Psoriasis, the Arthrite rhumatoïde, the Pseudo rhizomelic polyarthritis (PR) and the Maladie of Crohn. In the case of arthritis rhumatoïde, the concomitant use with the Infliximab or the étanercept strongly decreases symptomatology. (Klareskog, and Al , 2004)

the méthotrexate is used in the treatment of the molar diseases, and of the trophoblastic tumors , in particular the Choriocarcinome S. It also sometimes is used, although not recorded for this indication, to stop the early Grossesse S or ectopic.

It is managed orally, in injection Intramusculaire, Intraveineuse or Intrathécale, at frequency weekly rather than daily, which decreases certain side effects of them. one can also inject it under cutaneous

Side effects

The high amounts of méthotrexate used in anti-cancer Chimiothérapie can induce toxic effects on the cells with fast proliferation, such as the cells of the osseous Moelle and those of the digestive Muqueuse

hematopoietic Toxicity

Anemia
Neutropenia
Thrombopénie, with increased risk of Bruise S

digestive Toxicity

Mucite
Nausea

There exists also a pulmonary increased risk of Fibrose, and rarer cases of Hépatite.

Lastly, not to ignore, the overdoses in méthotrexate, which were described in France, in Germany, in the United States, in Great Britain, in Japan. They are due to errors, of which most frequent is the catch day laborer of méthotrexate, instead of its weekly catch, when this one is done by oral way. The principal signs of overdose are the fever, dry cough, the breathlessness, possibly followed pneumopathies; ulcerations of the mucous membranes; cutaneous lesions; thrombopénies and pancytopénies. The regulation, the delivery, the observance and the conditioning of the treatment must be rigorously controlled to prevent these overdoses which lead to the death if they are not detected sufficiently early.

Toxicity on the cells with fast proliferation is often prevented by " sauvetage" (folinic administration of Acid, not to confuse with the Folic acid ) or when the blood concentration in méthotrexate is higher than 0.1 µmol/l.

The méthotrexate is highly teratogenic (anomalies of closing of the tube neural) and interdict during the pregnancy or of breast feeding. It is also disadvised having sexual relations with a man taking of the méthotrexate without effective Contraception .

After the stop of méthotrexate, it is to better let pass a complete cycle ovulatoire at the woman, or three months at the man.

Mechanism

The méthotrexate inhibits the Dihydrofolate réductase, a Enzyme catalyzing the conversion of the Dihydrofolate into Tétrahydrofolate, the form activates folate. It is thus about an inhibition of the way of the Folate S as of its first stage.

Tetrahydrofolic acid N5-N10 methylene being necessary to the synthesis of novo Purin S and Thymidine, the méthotrexate inhibits the synthesis of DNA. By doing this, it also inhibits, in form polyglutamylée, the Amidophosphoribosyl transférase, and increases the intracellular rate of Phosphoribosyl pyrophosphate (PRPP).

The tetrahydrofolic Acide 5-methyl is used as donor of Méthyle for the regeneration of Méthionine starting from Homocystéine, methionine being adénosylée in S-adénosyl methionine, donor of methyl for the DNA, the Protéine S,… the méthotrexate thus disturbs these functions

In short, the méthotrexate is cytostatic selective of the phase S of the cellular replication, more credit on the cells with fast proliferation (like the malignant cells or myéloïdes, thus inhibiting their growth and their proliferation.

The inhibition of the amidophosphoribosyl transférase is not specific to the MTX: the polyglutamylés dihydrofolates exert this effect in a physiological way. They stimulate the synthesis of novo thus Pyrimidine S, as well as the way of recaptures purins. However, this effect decreases when the cells enter in phase of replication, since the intracellular rate of Dihydrofolate tends to decrease to provide the Tétrahydrofolate necessary to the nucleotidic synthesis .
En contrast, the méthotrexate exerts a persistent inhibition, even with low dose, which explains its anti-inflammatory drug effect.

References & notes

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