ssrpk
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S phase
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| Roxanita
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S phase.
DNA Replication by the semiconservative mechanism occurs in the S phase; this requires the de novo synthesis of DNA. Methotrexate inhibits dihydrofolate reductase, preventing the reduction of folic acid to produce tetrahydrofolate.
Tetrahydrofolate derivatives are used as a source of one-carbon moieties in purine nucleotide synthesis and in the methylation of dUMP to form dTMP.
Thus, by inhibiting dihydrofolate reductase, methotrexate also obstructs one-carbon metabolism, and deprives DNA polymerase of essential substrates. As a consequence, methotrexate is an antimetabolite that inhibits DNA synthesis in the S phase of the cycle.
The S phase is also the primary interval during which the other antimetabolites used in cancer chemotherapy act. These include:
Mercaptopurine and thioguanine (both purine analogues that inhibit purine synthesis)
Azacytidine (limits pyrimidine synthesis by inhibiting orotidylate decarboxylase)
Hydroxyurea (inhibits formation of deoxyribonucleotides from ribonucleotides), 5-Fluorouracil (inhibits thymidylate synthase) and
Cytarabine (AKA cytosine arabinoside, which inhibits DNA polymerase).
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