Brequinar sodium (DUP-785) is a potent inhibitor of the
pyrimidine de novo
enzyme, dihydroorotic
acid dehydrogenase (DHO-DH). In order to determine whether in vitro data could be extrapolated to the in vivo situation we investigated antipyrimidine effects of
DUP-785 in mice bearing
colon cancer. Two
tumor models were used, Colon 26 and Colon 38, resistant and moderately sensitive to
DUP-785, respectively.
DUP-785 at 50 mg/kg caused a depletion of plasma
uridine in mice, and depleted tissue
uridine levels in Colon 38 down to 10%, which was retained for several days; in Colon 26 the decrease was less and tissue
uridine levels recovered rapidly. In livers of these mice no significant effect on
uridine was observed.
DUP-785 depleted
UTP in bone marrow cells within 2 hr to 25% of control levels, after 4 days normal levels were found. In livers of both Balb-c mice (bearing Colon 26) and C57Bl/6 mice (bearing Colon 38) a small decrease of
uridine nucleotide pools was found. In Colon 26
DUP-785 increased
uridine nucleotide pools to 170% after 2 hr, at 1 day normal levels were observed, but after 2 days again an increase was found. In Colon 38
DUP-785 decreased the
uridine nucleotide pool by 50% after 1 and 2 days.
DUP-785 did not affect
cytidine nucleotide pools of livers and of Colon 26 and Colon 38. The ratio between
uridine nucleotides and
cytidine nucleotides decreased from 2.2 to 0.90 in Colon 38, in the other tissues the decrease was less. DHO-DH was measured in bone marrow cells and Colon 26 and 38 before and
after treatment. Basal levels of DHO-DH were 3 times higher in Colon 26 than in Colon 38. In treated
tumors DHO-DH was initially inhibited by more than 90%, after 7 days
enzyme activity in Colon 26 was 50% and in Colon 38 about 200% of basal levels. In bone marrow cells DHO-DH was also rapidly inhibited but recovered within 4 days. It is concluded that the retention of antipyrimidine effects of
DUP-785 in Colon 38 were more pronounced than in Colon 26, which is in agreement with the better antitumor effect of
DUP-785 in Colon 38.