Structural Biochemistry/Methotrexate

 Methotrexate 

Description
An chemotherapy drug used to treat cancer patients with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase, which helps with the formation of RNA. It also inhibits thymidilate synthetase, which is necessary for synthesis of DNA.

Usage


Methotrexate is used as a treatment for breast, head and neck, lung, stomach, and esophagus cancers, Acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), gestational trophoblastic cancer, and mycosis fungoides (cutaneous T-cell lymphoma). Methotrexate is given:
 * As an infusion into the vein
 * As an injection into the muscle
 * Another method it is given is by intraventricular or intrathecal infusion in which it is infused directly into the spinal fluid.
 * As oral form

Side effects

 * Low blood counts
 * Mouth sores
 * Nausea and vomiting
 * Kidney toxicity
 * Skin rash, reddening of the skin
 * Diarrhea
 * Hair loss
 * Eye irritation
 * Loss of fertility

Mechanism of action


Cancerous cells differ from normal cells in their cell division. When normal cells come in contact with cells that are identical to them, they stop dividing. This mechanism is known as contact inhibition. Cancerous cells do not have this ability. Cancer cells have no limit in cell division, which leads to the formation of tumor. Similar to normal cells, cancerous cells also go through a cell cycle, which consists of a resting phase, active growing phases, and mitosis.

Chemotherapy is able to kill cancer cells by damaging the DNA or RNA that are responsible for cell division. If the cancer cells cannot divide, the tumor will shrink. Chemotherapy drugs can be effective to dividing cells, which are called cell-cycle specific; or to cells that are at rest, which are called cell-cycle non-specific. Chemotherapy schedule is assigned based on the type of cancer cells and the rate at which they are dividing.

However, chemotherapy drugs cannot distinguish between the cancerous cells and the normal cells, which leads to the side effects. The normal cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss.

Methotrexate are classified as antimetabolites. Antimetabolites are very similar to normal cellular materials. When antimetabolites are taken into the cellular metabolism, they will compete with the normal cellular materials and inhibits certain pathways and eventually cell division. Methotrexate achieve its chemotherapeutic effect by being able to compete with folic acid in cancer cells, which results in folic acid deficiency in the cells and causing their death. Methotrexate also competes with folic acid in normal cells and causes significant side effects such as low blood cell counts, hair loss, mouth sores, diarrhea, liver, lung, nerve and kidney damage.

Methotrexate’s chemotherapeutic effects are a result of its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase and thymidylate synthetase. It enters cells through an active transport system used by folic acid. Methotrexate will then undergo polyglumatation. MTXGlu is even more effective in inhibits the enzymes. The enzyme Dihydrofolate Reductase maintains the level of reduced folic acid by reducing dihydrofolic acid which has been produced during thymidylate synthesis. Dihydrofolate reductase reduces folic acid to tetrahydrofolate, an essential co-factor in the synthesis of purine nucleotides.

Reference
"Methotrexate." Scott Hamilton CARES Initiative. N.p.. Web. 21 Nov 2012. 

Tian, Henghe, and Bruce N. Cronstein. "Bulletin of the NYU Hospital for Joint Diseases." Bulletin of the NYU Hospital for Joint Diseases. 65.3 (2007): 168-73. Print.

Brigitte C. Widemanna, Peter C. Adamson b. Understanding and Managing Methotrexate Nephrotoxicity Pediatric Oncology 2006;11;694-703.