The molecular correlation concept proposed that
IMP dehydrogenase activity should be a sensitive target of
chemotherapy. This hypothesis received support from an array of evidence.
IMP dehydrogenase has the lowest activity in
purine biosynthesis; it is the rate-limiting
enzyme in
GTP production; the enzymic activity is transformation-and progression-linked; it is elevated in all examined animal and human neoplastic cells. The activity of
GMP synthetase and the concentrations of GMP and
dGTP were increased in
cancer cells. Whereas
guanine salvage has a high potential activity, the low
guanine content may well curtail actual salvage capacity.
Ribonucleotide reductase activity was two orders of magnitude lower than that of
IMP dehydrogenase.
Tiazofurin, a C-
nucleoside, had marked cytotoxicity on
hepatoma cells in vitro and was the first
drug that as a single agent profoundly inhibited the proliferation of the subcutaneously inoculated solid
hepatoma 3924A in the rat. The impact of
tiazofurin administration in
hepatoma cells was revealed in a cascade of biochemical alterations involving primary, secondary and tertiary targets and markers of this
drug action. The primary target was
IMP dehydrogenase where the active metabolite of
tiazofurin, TAD, was thought to be absorbed to the
NADH site of the
enzyme. As a consequence, the enzymic activity declined rapidly to about 30-40% and returned to normal range by 36 to 48 hr after injection. The secondary targets and markers are the profoundly decreased pools of guanylates (GMP,
GDP,
GTP). Concurrently, the concentrations of
IMP and PRPP were increased 8- to 15-fold. The elevated
IMP pools were attributed to the de-inhibition of the
AMP deaminase activity subsequent to the decline in
GTP concentration. The rise in PRPP pools was attributed to the selective inhibition of GPRT and
HPRT activities by the high
IMP pool which did not affect APRT activity. This interpretation is supported by the 6- to 8-fold increase in the concentrations of
guanine and
hypoxanthine and the lack of change in the
adenine pools inthe
hepatomas after
tiazofurin administration. The marked drop in
NAD concentration which was
drug dose- and time-dependent is attributed to the competition for
NAD pyrophosphorylase activity by the precursors of
NAD and
tiazofurin monophosphate. The tertiary targets were dominated by the profound alterations in the concentrations of the dNTPs. This was characterized by a rapid and persistent drop (for 3 days) of the
dGTP pool. The concentrations of dATP and
dCTP also declined, but these alterations were less pronounced and the pools returned to normal after 2 days.(ABSTRACT TRUNCATED AT 400 WORDS)