MTX Mechanisms Indications and Toxicities

Mechanisms: Inhibits both dihydrofolate reductase (DHFR) and thymidine (thymidylate) synthetase, making reduced folate (folic acid) unavailable for DNA and RNA synthesis. Indications: Lymphoma, lymphocytic leukemia, breast cancer, small cell carcinomas, gesta-tional trophoblastic disease, rheumatoid arthritis, psoriasis, suppression of organ transplant rejection.

Toxicities: Gastrointestinal > renal > bone marrow > CNS > pulmonary:

Gastrointestinal: Nausea, vomiting, mucositis = stomatitis, esophagitis, diarrhea; hepa-totoxicity = increased hepatic transaminases (AST/ALT).

Renal: Oliguria and azotemia = acute renal failure.

Bone marrow: Pancytopenia. CNS: Seizures, hemiparesis. Pulmonary: Delayed (by 12-17 years) hyper-sensitivity pneumonitis.

MTX inhibits both dihydrofolate reductase & thymidylate synthetase

2-Deoxyuridine monophosphate

^ymidylate synthetase


* Dihydrofolate reductase (DHFR)

* Dihydrofolate reductase (DHFR)

n5, 10, 10 - Methylene Fh4 (Tetrahydrofolate)

^ymdylate -

Purines i

DNA/RNA Synthesis n5 - Formyl FH4 (Leucovorin)

FIGURE 11.4 The mechanisms of action of metho-trexate (MTX). The anti-neoplastic activities and sites of action of the commonly prescribed cancer chemo-therapeutic agent, methotrexate (MTX).

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