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Haley Felts
(April 27, 2015)


Cancer is a much discussed topic in the medical world. Despite its popularity, cancer treatments are not well understood to those who don’t work in this field. Chemotherapy is one of the main forms of treatment for cancer. It is used as a means to cure, shrink, and prevent cancer (Chen, 2014). The use of chemotherapy is usually paired with radiation therapy either at the same time, before, or after (Chen, 2014). There are many different chemotherapy drugs used, and the type that is administered depends on the type of cancer that the patient has. For childhood acute lymphoblastic leukemia (ALL), methotrexate is a chemotherapy drug that is used. One of the main reasons that methotrexate is used to treat ALL is that it helps prevent the cancer from spreading to the central nervous system; it is also used to treat ALL if it has spread to the CNS (National Cancer Institute, 2013). Many parents of cancer patients wish they knew more, understood more, and had access to information that doesn’t sound alien. Hopefully, through this article those parents and everyone will know and understand the different aspects and properties of one of the many chemotherapy drugs, methotrexate. 


Chemical Description


(National Center for Biotechnology Information, 2005)

Methotrexate is considered an anti-metabolite drug (National Center for Biotechnology Information, 2005). There are several trade names for it as well: Abitrexate, Folex PFS, Folex, Methotrexate LPF, Mexate-AQ, and Mexate (National Cancer Institute, 2013). The molecular weight for methotrexate is 454.43928 g/mol (National Center for Biotechnology Information, 2005). Also, the molecular formula for it is C20H22N8O5 (National Center for Biotechnology Information, 2005). The appearance of methotrexate is described as an orange-brown, crystal-like powder (Lewis, 1997). Methotrexate has a melting point of 195oC, and a pKa of 4.7 (National Center for Biotechnology Information, 2005). If methotrexate is heated to its point of decomposition, it will release toxic fumes (fumes that may include nitrogen oxides) (Lewis, 1996). The main active ingredient in methotrexate is methotrexate sodium (National Center for Biotechnology Information, 2005). It is usually given as a prescription and administered via oral tablet or injection (National Center for Biotechnology Information, 2005). It belongs to several classes of drugs, including the following: antineoplastic agents, antipsoriatic, antirheumatic, and cytotoxic drugs (National Center for Biotechnology Information, n.d.). Methotrexate should be stored in an area without light and in tightly closed containers that are in a 15-30oC environment (National Center for Biotechnology Information, 2005).


Uses and History

Methotrexate has been used before to help treat rheumatoid arthritis (Cronstein, 2007). As mentioned previously, another main use is as a chemotherapy drug primarily to treat ALL (National Cancer Institute,, 2013). Methotrexate is often used to treat ALL if it has spread to the central nervous system (CNS) or to prevent its spreading to that region (National Cancer Institute,, 2013). There is a high risk of ALL spreading to the CNS, and sometimes it has spread there even before diagnosis (American Cancer Society “Typical ..”, 2015). The reasoning behind using methotrexate as a primary treatment/prevention of ALL spreading to the CNS is that in high doses it has the ability to cross the blood-brain barrier (BBB) unlike most chemotherapy drugs (Cassels, 2008). Thus, it can actually reach the brain to treat the cancerous cells that have spread there.


Routes of Exposure and Metabolism

There are various methods by which methotrexate is administered. It can be taken in pill form (National Center for Biotechnology Information, 2005). When administered as a chemotherapy drug, it can be given using various routes of exposure. These routes include into the muscles, injection under the skin, intravenous, injection into an artery, pills, and injection into the spinal or cerebrospinal fluid (Chen, 2014). If chemotherapy is administered over an extended amount of time a catheter will be inserted into a vein near the heart (Chen, 2014). The amount of time considered extended would depend on the circumstances of the drug used and the aggressive qualities of the cancer. However, chemotherapy for ALL is typically given in three stages over the course of two years (American Cancer Society “Chemotherapy …”, 2015). Generally it is absorbed the best when given orally or intramuscularly (Cronstein, 2007). This means that by those routes methotrexate enters/reaches the bloodstream the best. Due to the low pKa of this compound, oral exposure becomes one of the best routes of exposure. Intramuscular administration can help reduce the side effects that usually accompany oral administration (Cronstein, 2007). Food intake has no effect on the absorption when the route of exposure is oral (Cronstein, 2007). This fact is most likely due to the lipophilic nature of the compound and the small dosage of it. In oral exposure, reduced folate carrier 1 (RFC1) controls the uptake of methotrexate in the alimentary canal (Cronstein, 2007). Once absorbed, a small amount of methotrexate is transformed into 7-hydroxymethotrexate (Cronstein, 2007). This biotransformation occurs in the liver (Cronstein, 2007). Once methotrexate and 7-hydroxymethotrexate are transported into the cell, they are transformed again into polyglutamate derivatives (Cronstein, 2007). Considering that methotrexate is a folic acid antagonist, it works to block the production of pyrimidines and purines by stopping the enzymes that help in the production (Cronstein, 2007). Pyrimidines and purines are found in DNA; they are the nucleic acids that are the building blocks of DNA. This inhibition of enzymes also leads to weakened DNA methylation, disrupting DNA synthesis, and blocking de novo purine synthesis (Cronstein, 2007). In other words, methotrexate mimics purine or pyrimidine and stops the production of DNA, which prevents cell development and division (National Center for Biotechnology Information, 2005).


Human Health Effects

Methotrexate has various effects on childhood acute lymphoblastic leukemia (ALL) considering that it is primary chemotherapy drug used to treat it (National Cancer Institute, 2013). Childhood ALL is a cancer in the blood and bone marrow (National Cancer Institute, 2015). In this form of cancer too many stem cells become white blood cells, and these are not healthy white blood cells (National Cancer Institute, 2015). These white blood cells can’t fight infection and microbial invaders as well as normal cells (National Cancer Institute, 2015). As the amount of cancerous white blood cells increases, especially in the bone marrow, there is less room for the healthy blood cells (meaning healthy white blood cells, red blood cells, and platelets) (National Cancer Institute, 2015). This unhealthy growth and lack of healthy blood cells can lead to infection, anemia, and easy bleeding (National Cancer Institute, 2015). There are several ways in which childhood ALL is identified to determine that one does in fact have cancer. These examinations include the following: physical exam and review of history, complete blood count, blood chemistry studies, bone marrow aspiration and biopsy, cytogenetic analysis, immunophenotyping, and a lumbar puncture (National Cancer Institute, 2015). Childhood ALL is the most common form of cancer in children and it must be treated quickly (National Cancer Institute, 2015).

Since methotrexate is a chemotherapy drug, the usual chemotherapy side effects do have the possibility of occurring. These side effects include increased risk of infections, tiredness, easy bleeding, pain from damaged nerves, dry mouth, mouth sores, swelling in the mouth, bad appetite, weight loss, nausea, vomiting, diarrhea, or loss of hair (Chen, 2014). There is also the possibility that methotrexate treatment will lead to bone marrow suppression, liver toxicity, and stomatitis (Cronstein, 2007). These side effects primarily occur as a result of the disruption of purine and pyrimidine synthesis, which is caused by methotrexate (Cronstein, 2007). The lack of purine and pyrimidine synthesis causes a lack in the growth of new healthy cells. The lack of new cells would cause liver toxicity because the liver would not have new available healthy cells to regenerate itself, and this concept applies to all of the other side effects since those regions rely on new cells for regeneration as well.


Regulation and Precautionary Notes

Methotrexate is primarily regulated by prescription (National Center for Biotechnology Information, 2005). Due to the nature by which it is used, prescription is the only way it can be obtained. Also as a chemotherapy drug, it is administered and regulated under the supervision of doctors, nurses, and other clinical professionals.

Due to all of the toxicities that occur following the treatment of methotrexate, it is advised to take a folic acid supplement to help prevent/treat these toxic responses (Cronstein, 2007).



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