Resources and information for parents of children with cancer . . . by parents of children with cancer.

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Note: This section has health/medical information. It was not written by a health care professional, however, the author has an MS in biochemistry and has a good knowledge of drugs and how they work. The medical references are at the bottom of this page.

say: meth-oh-TREX-ate

Methotrexate is a chemotherapy drug used to treat leukemia, lymphomas, and osteosarcoma. It is also used in the treatment of AIDS and rheumatoid arthritis, which is of interest because you can find information on this drug on the Web at sites relevant to these diseases as well as cancer sites.

How it's administered

Methotrexate is given IV (intravenous), PO (orally), IM (intramuscular), and IT (intrathecal; spinal).

When and how to give oral methotrexate

PO (oral). Oral methotrexate should be given at least an hour after the evening meal; some sources say two hours after a meal. Do not give with milk. Give it just before bed, since your child should not eat for an hour after taking it.

IT (intrathecal; spinal). IT methotrexate is given in the hospital clinic under the doctor's supervision.

IV (intravenous). Some protocols call for high-dose IV methotrexate. This is usually administered in the hospital. Before administration, your child will need to be well-hydrated. Drinking fluids helps, but it's often done IV. During methotrexate administration and just after, your child will be monitored for drug elimination, hydrated, and treated with leucovorin (see below). Some parents report that they asked for or were given the option to do the entire methotrexate IV treatment or at least the hydration part at home, with the child wearing a backpack for the IV containers. If you are comfortable with this, do ask your doctor if you can do it at home. If you are not, don't let them force you to do it at home.

IM (intramuscular). IM methotrexate is given at the hospital clinic. Occasionally, a parent is given the dose to be administered by a non-clinic nurse, for instance, if the family is going on vacation.

Doses in ALL trials: High dose (HD) vs low dose

POG protocols: IV ID methotrexate is1g/m2, HD is 2.5g/m2, as given IV over 4-24 hours, usually with leukovorin rescue. CCG protocols that include "escalating" IV methotrexate administer it 0.10 g/m2 over 10-15 min, then escalate each subsequent dose by 50mg/m2/dose to toxicity. When given PO, methotrexate is 15-20 mg/m2/day in maintenance. POG employs 4 PO doses of mtx, each 25mg/m2, for 100mg/m2/day in intensive continuation.

Drug interactions

Side Effects

Common side effects.

Less common side effects:

(All of the adverse effects reverse when the drug is discontinued. The above listing of side effects was taken from hospital obtained instruction sheets, Web sites, as well as Nancy Keene's book, Childhood Leukemia.)

The parents' version of side effects:

In an informal survey of online groups, at least one parent reported observing at least one of the each of the above side effects in their child, with perhaps the exclusion of lung, liver, and kidney damage. (Damage to these organs is monitored by the oncologists and chemo adjusted accordingly; damage can show up long after chemo is discontinued; other chemo agents can also cause damage, so it's hard to pinpoint what caused it. Hair loss and immunosuppression too can be caused by multiple agents. Liver and kidney function is more likely to be affected with IV doses.)

One parent's child in the online discussions had a stroke attributed to methotrexate -- see the discussion the section on parents comments on side effects. There is some concern that seizures can be attributed to IT methotrexate -- see the parent comment under IT methotrexate.

The above side effects differ widely according to the dose and the method of administration. So, I'll break them down according to PO, IT, IV, and IM.

Side effects of oral methotrexate

With oral doses, most parents report nausea and skin and eye sensitivity to sunlight. Here are some additional comments:

Side effects of IT methotrexate

IT treatment usually results in tiredness, headache, backache, spinal cord irritation. IT methotrexate is often given with other IT drugs or IV drugs; it can be hard to attribute effects to the methotrexate, or even to the anaesthesia used to sedate the child. After spinals, kids usually feel tired, for at least the rest of the day, perhaps into the next as well. Side effects have also been attributed to the rate at which the spinal is administered; a doctor who gives the doses slowly is prized by parents because the kids feel fewer headaches.

Side effects of IV methotrexate

Side effects of IM methotrexate

Most of the complaints about IM methotrexate stem from the shot itself:

Rare but documented side effects include seizures and strokes. A stroke happened to a two year old boy being treated with methotrexate for lymphoma. His mom wrote the following:

"The things I would like parents to know:

Three references pulled from MEDLINE concerning seizures/strokes:

Special precautions to take while your child is taking methotrexate

Your child must wear sunscreen while outside. And, don't forget sunglasses! The eyes are more sensitive to the damaging rays of the sun when methotrexate is being given.

If you are giving your child vitamins, find some without added folic acid. Here are some suggestions from the online groups:

To stave off the ill effects, your child should drink at least 2 quarts of high calorie fluids such as juices and nectars per day.

Avoid use of over-the-counter drugs without first consulting with your doctor or pharmacist.

Methotrexate: How it works

A section by the editor, playing chemist.

Here is the structure of methotrexate:



The CA name for methotrexate is: N[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid. The CA registry number is 59-05-2. Common synonyms: Mexate, Methylaminopterin, Emtexate, Metatrexan, Methopterin, MTX dihydrate, Folex, Folex PFS, Amethopetrin.

Methotrexate is an antineoplastic, an antirheumatic, a nucleic acid anti-metabolite (like 6-MP,above), and a "folic acid antagonist".

Hmm, folic acid, a necessary nutrient. Let's see, here's folic acid, let's compare:

folic acid

You can see that the nitrogen group has a CH3 on it and there is an OH group in the double ring instead of an NH2 group. Enough to make a difference in a biosynthesis scheme!

At two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer reactions occur which require specific coenzymes.These coenzymes are synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it thinking that it is folic acid. In fact, methotrexate looks so good to the enzyme that it binds to it quite strongly. All the folic acid reductase enzymes in the cell bind merrily to the methotrexate and ignore any folic acid they might see. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Again, without DNA, no cell division.

Most of the parents of cancer kids have been told not to give folic acid supplements during chemo since it interferes with the action of the methotrexate.

Methotrexate has a general toxicity because it affects all rapidly dividing cells, such as those in the intestonal mucosa and prevents the production of tetrahydrofolate from folic acid in all tissues. Tetrahydrofolate is a necessary compound in many biosynthetic pathways, not just the synthesis of DNA. One of these is the synthesis of L-glutamate. One parent told us that her oncodoc recommended glutamic acid supplements, and that they helped her child immensely. Makes sense.

Also listed by the hospital: the possible adverse effects of this drug are mouth lesions in the form of painful patches on the lips, gums and mucosa of the mouth. These clear rapidly with stopping the drug. Along with mouth ulcers, there can also occur ulceration of other parts of the digestive tract with abdominal pain, vomiting and diarrhea. This drug can depress the bone marrow, which leads to a depression of white blood cells, platelets, and red blood cells.

Which means that they will be monitoring your child's CBC. With high doses of methotrexate, they will monitor fluid intake and urine output closely. Leucovorin is a medicine that may be prescribed. Leucovorin is an antianemic and an antidote for folic acid antagonists. Leucovorin is the active form of the B complex vitamin, folate. Another name for Leucovorin is folinic acid: the very name I found in a biochem text - it said that it could help alleviate the effects of methotrexate! "Leucovorin is used as an antidote to drugs that decrease levels of folic acid. Folic acid helps red and white blood cell formulation and the synthesis of hemoglobin. Some treatments require what is called leucovorin rescue, because the drug used to treat the cancer or other infection has had an adverse effect on folic acid levels. Leucovorin is used to reduce anemia in people taking dapsone, a preventive treatment for PCP. Leucovorin is also used in combination with chemotherapy such as methotrexate." (The words in "" are from the link on Leucovorin given above.)


Biochemistry/oncology texts. Web sites accessed 2011. I also refered to our COG protocol (1961) and the drug sheets we received with the drug.

General Disclaimer

These pages are intended for informational purposes only and are not intended to render medical advice. The information provided on Ped Onc Resource Center should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you suspect your child has a health problem, you should consult your health care provider.

© copyright 1998-2018 by Patty Feist

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