A single injection of the anti-
glutamine drug,
acivicin (
NSC 163501), in
tumor-bearing rats in 30 min decreased the activities of
amidophosphoribosyltransferase,
carbamoyl-phosphate synthetase II and
CTP synthetase to 56, 50, and 7% of those of the controls. By 1 hr the activities were down to 32, 13 and 3% and they remained low for 12 hr, after which they slowly returned towards normal range in 72 hr. The decline of the activity of
CTP synthetase (a loss of 80% in 10 min) was the most rapid, and the activity only returned to 60% of the controls by 3 days after the
acivicin injection. In the
hepatoma the concentrations of
ATP and
UTP changed little, but those of
GTP and
CTP rapidly decreased, reaching at the lowest point 32 and 2%, respectively, of control values 2 hr after
acivicin; concentrations started to rise at 12 hr, reaching normal levels by 48 hr. The drop in
enzyme activities preceded the decline in the pools of
GTP and
CTP. The behavior of
enzyme activities and
nucleotide concentrations in the host liver had a pattern similar to that in the
hepatoma; however, the changes were less extensive than those in the
tumor. The differential response between
tumor and liver is attributed, in part at least, to the tissue
L-glutamine concentration which in the
hepatoma (0.5 mM) was 9 times lower than in the liver (4.5mM). The selectivity of
acivicin action in inhibiting
glutamine-utilizing
enzymes is also demonstrated by the lack of effect on
aspartate carbamoyltransferase, an enzymic activity which resides in the same complex as that of
carbamoyl-phosphate synthetase II. The rapid decline in the activities of
glutamine-utilizing
enzymes is attributed to an inactivation of the
enzymes by
acivicin which functions as an active sitedirected affinity analog of
L-glutamine. The rapid modulation of the enzymic phenotype and
ribonucleotide concentrations by
acivicin provides a useful tool for elucidating the role of enzymic and
nucleotide imbalance in the commitment of
cancer cells to replication and in the targeting of anticancer
chemotherapy.