Methotrexate, leucovorin, 5-fluorouracil, hydroxyurea

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Anti-metabolites, such as methotrexate, leucovorin, 5-fluorouracil, and hydroxyurea, are molecules that exert their antiproliferative effects by imitating the intermediates involved in various steps of nucleic acid metabolism. These actions either disrupt DNA synthesis or impede cell growth, which allows these agents to control the proliferation of rapidly dividing cells, such as cancer cells.

Methotrexate functions as a folate analog, inhibiting the enzyme dihydrofolate reductase and thereby halting DNA synthesis. Its application is widespread, notably in the treatment of leukemias, lymphomas, and various other malignancies. Leucovorin, a reduced form of folate, is used to counteract the toxic effects of methotrexate, particularly in cases of bone marrow, gastrointestinal, and mucosal-related toxicity.

5-fluorouracil (5-FU) is a pyrimidine analog that inhibits the enzyme thymidylate synthase, which disrupts thymidine synthesis and impedes DNA synthesis. It's primarily used to treat colorectal cancer and other solid tumors. However, it's important to note that 5-FU may cause acute gastrointestinal toxicity and various cutaneous complications, including photosensitivity reactions.

Hydroxyurea inhibits ribonucleotide reductase, which blocks the conversion of UDP to deoxy-UDP. This then prevents thymidine synthesis (which inhibits DNA synthesis) and arrests the cell in the S phase of the cell cycle. Hydroxyurea can be effective in treating acute and chronic myelogenous leukemia, as well as reducing veno-occlusive crises in sickle cell anemia.

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1. What is the mechanism of action of methotrexate, and what conditions is it used to treat?

Methotrexate (MTX) is a cytotoxic folate analog. It irreversibly blocks the enzyme dihydrofolate reductase, which inhibits the tetrahydrofolate synthesis, and thus inhibits DNA synthesis and cell division. It has a wide therapeutic range, and is used to treat malignancies such as leukemias, lymphomas, breast cancer, head and neck cancer, and lung cancer. It is also used to treat ectopic pregnancy, invasive molar pregnancy, and psoriasis, and is a first line treatment for rheumatoid arthritis. Furthermore, MTX is useful for immunosuppressive therapy in the treatment of IBD, SLE, vasculitis, dermatomyositis.

2. What are the implications of using 5-fluorouracil in cancer treatment?

5-fluorouracil (5-FU) is a cytotoxic pyrimidine analog that binds to THF and inhibits thymidylate synthase, thus inhibiting thymidine production and DNA synthesis. 5-FU has activity against many solid tumors including colorectal, breast, head and neck, liver, pancreas, and basal cell cancers. However, unlike with methotrexate, leucovorin (folinic acid) does not prevent the toxicities of 5-FU, which can include diarrhea, and a variety of cutaneous complications.

3. How do methotrexate, 5-FU, and hydroxyurea interfere with DNA synthesis?

All three drugs act to inhibit DNA synthesis by blocking the production of thymidine, which necessary for DNA synthesis. They do this in different ways: Methotrexate and 5-FU are antimetabolites that inhibit enzymes necessary for the synthesis of thymidine (methotrexate inhibits dihydrofolate reductase while 5-FU inhibits thymidylate synthase), whereas hydroxyurea inhibits ribonucleotide reductase, which stops the conversion of UDP to deoxy-UDP, a process which is also crucial for thymidine production and DNA synthesis. The general result is blockage of the S phase of cell cycle (where DNA replication occurs).

4. What are the major toxicities of methotrexate, and how can they be counteracted?

Methotrexate can cause a range of severe side effects including folate deficiency, megaloblastic anemia, myelosuppression and pancytopenia, immunosuppression, pulmonary fibrosis, hepatotoxicity, alopecia, and mucositis. Leucovorin (folinic acid) treatment--- also known as "leucovorin rescue"--- can be used to reverse the toxic effects of methotrexate.

5. What is the role of hydroxyurea in the treatment of malignancies and other disorders?

Hydroxyurea is a ribonucleotide reductase inhibitor that blocks the synthesis of thymidine, thereby inhibiting DNA synthesis. It has activity against solid and hematologic malignancies such as AML, CML, and head and neck cancer. It is also useful in reducing veno-occlusive crises in sickle cell anemia by increasing levels of fetal hemoglobin which protects against polymerization of the mutated HbS variant.