F-dUMP

Fluorouracil (5-FU) acts as a false pyrimidine, inhibiting the formation of the DNA base thymidine.26,35 The main mechanism by which it accomplishes this is by inhibiting the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. 5-FU first must be metabolized to its active metabolite (F-dUMP). Additionally, metabolites of 5-FU may incorporate into RNA, inhibiting its synthesis. 

Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively. Human cells are unable to convert the parent drug to its active metabolites. 

Many drugs have been developed to intervene in the synthesis of TMP (Figure 6.24). For example, methotrexate (6.66) inhibits DHFR by blocking the binding site of DHF. Another antimetabolite, 5-fluorouracil (5-FU, 6.67), is converted in the body to 5-fluoro-2 -deoxyuridine 5 -monophosphate (F-dUMP, 6.68), a potent inhibitor of TS.26... 

Pluorouracil is a pyrimidine analog which is converted metabolically to its toxic form, fluorodeoxyuridylate (F-dUMP). As cells metabolically activate the drug it acts as a "suicide" inhibitor of Thymidyiate Synthetase. 

Colin Tuma is being treated with 5-fluorouracil (5-FU), a pyrimidine base similar to uracil and thymine. 5-FU inhibits the synthesis of the thymine nucleotides required for DNA replication. Thymine is normally produced by a reaction catalyzed by thymidylate synthase, an enzyme that converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). 5-FU is converted in the body to F-dUMP, which binds tightly to thymidylate synthase in a transition state complex and inhibits the reaction (recall that thymine is 5-methyl uracil). Thus, thymine nucleotides cannot be generated for DNA synthesis, and the rate of cell proliferation decreases. 

Clinicians who use F-dUMP and methotrexate together in cancer treatment find that the combined effects on cancer cells are not synergistic. Suggest how the administration of methotrexate could interfere "with the action of F-dUMP. 

Amarouche M, Gadea F, Dump J (1989) A proposal for the theoretical treatment of multi-electronic-state molecular dynamics hemiquantal dynamics with the whole dim basis (HWD). A test on the evolution of excited ar3- - cluster ions. Chem Phys 130 145-157... 

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