CLINICAL CASES
33
[3.4]
Leukemia patients are often given the compound Leucovorin
(N5-formyl THF) following treatment with the drug methotrexate. Why
is Leucovorin useful as part of this treatment protocol?
A. It facilitates the uptake of methotrexate by cells
B. It can be converted to THF by bypassing DHFR
C. It acts as an activator of thymidylate synthase
D. It prevents the uptake of methotrexate by normal cells
E. It stimulates cells of the immune system
A nsw ers
[3.1]
B.
Megaloblastic anemia is caused by a decrease in the synthesis of
deoxythymidylate and the purine bases usually caused by a deficiency
in either THF or cobalamin or both. This results in decreased DNA
synthesis, which results in abnormally large hematopoietic cells cre-
ated by perturbed cell division and DNA replication and repair. This
patient exhibits signs of chronic alcoholism, which often leads to a
folate deficiency. This can occur due to poor dietary intake, decreased
absorption of folate due to damage of the intestinal brush border cells
and resulting conjugase deficiency, and poor renal resorption of folate.
[3.2]
D.
Bacteria must synthesize the folate that is required for their
biosynthetic processes; they do not have a transporter to bring folate
into the cell. Trimethoprim inhibits prokaryotic DHFR (eukaryotic is
not affected) and sulfamethoxazole is an analog of p-aminobenzoic
acid (PABA), a precursor to folic acid. Bacteria will use this analog
instead of PABA and produce a nonfunctional folate.
[3.3]
B.
Methotrexate inhibits the synthesis of deoxythymidine by pre-
venting the regeneration of THF by inhibiting the enzyme DHFR.
Inhibiting the synthesis of deoxythymidylate prevents the cell from
synthesizing its DNA. DNA synthesis occurs exclusively during
S phase of the cell cycle.
[3.4]
B.
Leucovorin (N5-formyl THF, folinic acid) is used as an antidote for
cells that have decreased levels of folic acid. Treatment of leukemia
patients with methotrexate kills the tumor cells but also other normal
rapidly dividing cells. N5-formyl THF is normally administered 24
hours following treatment with methotrexate; it can be converted to
THF by these normal cells by bypassing the block caused by
methotrexate.
Therefore,
these
normal
cells
can
synthesize
deoxythymidine and carry out DNA synthesis.
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