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Use the following passage to answer questions: In the 1950s, doctors demonstrated that methotrexate (MTX) could cause regression of metastatic gestational choriocarcinoma, a highly fatal cancer of the reproductive tract, paving the way to the first chemotherapeutic drug that shrinks solid cancer. Now MTX is used in the treatment of numerous cancers, including breast, lung, osteosarcoma, and leukemia. The original breakthrough arose from the observation that rapidly dividing cells such as tumor cells require folate to make thymine; experts thus reasoned that folate inhibitors could reduce the progression of cancer. MTX is a competitive inhibitor of dihydrofolate reductase (DHFR). By binding to the enzyme, MTX reduces its ability to convert dihydrofolate to folic acid, which is a step in a cellular pathway that is necessary for producing thymine. The association between MTX and DHFR has been shown to involve a complex process and several conformations of the enzyme.
However, studies have suggested that MTX acts not only by reducing the level of folic acid; the drug could also directly block the enzyme thymidylate synthase that converts the product of folic acid back to dihydrofolate and as a byproduct generates thymine (in its deoxyribonucleoside 5'-phosphate form, dTMP) from its precursor.
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