section
n i
Inhibitors of Purine Biosynthesis
627
analogue of aspartic acid isolated from fungi. By compet-
ing with aspartate, it inhibits adenylosuccinate synthetase
and hence the synthesis of AMP, it is an experimental an-
tineoplastic agent.
Mycophenolic acid
and
ribavarin monophosphate
in-
hibit IMP dehydrogenase and hence GMP synthesis.
Inhibitors of Multiple
Steps—Purine Analogues
6
-Mercaptopurine
is a structural analogue of hypoxan-
thine and is converted to thio-IMP in the salvage pathway.
Thio-IMP prevents production of AMP and GMP by in-
hibiting the following reactions:
G lutam ine + PRPP
*------------
0
5-P h osp h orib osylam in e
s O —
IM P-----------
i
------------XMP-
A d en ylosu ccin ate
\
i
\
i
Thio-IMP
1
i
J — I_____
i
GMP
AMP
6
-Mercaptopurine is used in the treatment of acute
leukemias. However, resistant tumor cells develop rapidly,
probably because of altered specificity or lack of phospho-
ribosyltransferases, so that thio-IMP (the active inhibitor)
is not formed. In support of this mechanism, resis-
tant cells respond to
6
-methylmercaptopurine ribonu-
cleoside, which is phosphorylated to the correspond-
ing nucleotide. Other mechanisms may include altered
cell permeability and increased rate of destruction of
6
-mercaptopurine.
6
-Mercaptopurine is partially metabolized to
6
-thiouric
acid (which lacks antitumor activity) by xanthine oxidase.
Allopurinol, a xanthine oxidase inhibitor used in the treat-
ment of gout, potentiates the action of
6
-mercaptopurine
by preventing its conversion to
6
-thiouric acid. This ef-
fect is taken into consideration in treatment. Mercaptop-
urines are also inactivated by S-methylation carried out
by thiopurine S-methyltransferase (TPMT), particularly
in hematopoietic tissues which lack xanthine oxidase. De-
ficiency of TPMT due to polymorphisms causes profound
toxicity with the regular therapeutic regime. This is an-
other example of the use of pharmacogenomics.
Azathiopurine,
a derivative of
6
-mercaptopurine, func-
tions as an antiproliferative agent. Its principal use is
as an immunosuppressive agent. It presumably releases
6
-mercaptopurine in the body by reacting with sulfhydryl
compounds such as GSH.
6-Thioguanine
6
-Thioguanine
is similar to
6
-mercaptopurine in its ac-
tion. The most active form is
6
-thio-GMP, which inhibits
guanylate kinase and, at higher concentrations, IMP de-
hydrogenase. Thio-IMP and thio-GMP also inhibit PRPP
amidotransferase.
Vidarabine
(adenine arabinoside), an analogue of
adenosine, does not interfere with purine biosynthesis but
affects DNA synthesis.
It is phosphorylated to adenine arabinoside triphosphate,
which inhibits viral DNA polymerases, but not the
