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FIGURE 2.16 Catalytic cycle of thymidylate synthase.

as dUMP. The strong electron-withdrawing effect of the fluorine atom increases the electrophilicity of the unsaturated carbonyl system and facilitates the formation of 2.26, but the final p-elimination reaction is not possible due to the presence of the fluorine atom at C-5 and therefore the ternary complex 2.27 is stable (Fig. 2.17). Because of the need for an activation step by nucleophilic attack of a cysteine residue of TS prior to enzyme inhibition, 5-FdUMP can be considered as a suicide inhibitor.

TS inhibition leads to depletion of TMP and subsequent depletion of dTTP, which induces alterations in the levels of other deoxynucleotides through various feedback mechanisms. These imbalances result in an alteration of the dATP/TTP ratio, among others, which disrupts DNA synthesis and repair and leads to the so-called thymineless death.18 A cytotoxicity mechanism alternative to TS inhibition is based on the generation of 5-fluoro-2'-deoxyuridine-triphosphate (5-FdUTP), which acts as a false substrate of DNA polymerase and is misincorporated into DNA. As a consequence of the accumulation of dUMP after TS inhibition, dUTP can also be generated and incorporated into DNA. Ultimately this change halts DNA synthesis and promotes DNA fragmentation by repair enzymes. Similarly, transformation of 5-FUDP, a metabolite of 5-FU, into the corresponding triphos-phate allows the misincorporation of fluoronucleotides into RNA, leading to profound effects on cell metabolism and viability. Both TS inhibition and misincorporation of 5-FU metabolites in DNA result in the stabilization of p53, a tumor suppressor that maintains DNA integrity by activating genes that arrest cell cycle in response to DNA damage or trigger apoptosis (Fig. 2.18). In vitro studies have proved that loss of p53 function is associated to a reduced sensitivity

The clinical efficacy of 5-FU may be decreased by several mechanisms, the first of which is diminished incorporation of 5-FUTP into RNA as a consequence of competition from high intracellular levels of UTP. On the contrary, the formation to 5-FU.19

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