Inhibition of this enzyme prevents the regeneration of THF and
blocks dTMP
because of the lack of the methyl donor required for the reaction of
thymidylate synthase.
THF is also required as a donor of two carbon atoms in the synthesis
of the purine ring structure required for adenine and guanine.
The carbon
atoms donated by THF are indicated in Figure 3-3. Therefore, a lack of THF
blocks the synthesis of the purine ring structure because of the lack of the abil-
ity of the cell to synthesize N10-formyl-THF.
In summary,
DNA synthesis requires synthesis of dTMP and the purines
adenine and guanine.
THF, derived from the
vitamin folic acid,
is required
for the biosynthesis of these nucleotides. Treatment with methotrexate blocks
the cell’s ability to regenerate THF, leading to inhibition of these biosynthetic
pathways. The lack of nucleotides prevents DNA synthesis, and these cancer cells
cannot divide without DNA synthesis. Unfortunately, the effects of methotrexate
are nonspecific and other rapidly dividing cells such as epithelial cells in the
oral cavity, intestine, skin, and blood cells are also inhibited. This leads to the
side effects associated with methotrexate (and other cancer chemotherapy
drugs) such as mouth sores, low white blood cell counts, stomach upset, hair
loss, skin rashes, and itching.
(amide N)
(amide N)
Figure 3-3.
Origin of the atoms of the purine base ring system (RP = pentose
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