3-Deazauridine (DAUrd), a competitive inhibitor of
CTP synthetase, inhibits both
RNA and
DNA synthesis. Murine
leukemia cells resistant to
cytosine arabinoside (
ara-C) due to a deletion of
deoxycytidine kinase are collaterally sensitive to DAUrd, which inhibits the de novo production of
CTP and hence results in
dCTP depletion. We evaluated DAUrd in combination with the
palmitate derivative of
ara-C (
palmO-ara-C) in mice bearing
L1210 leukemia cells with a subpopulation resistant to
ara-C. Both simultaneous administration and a sequential schedule of
palmO-ara-C at its maximally tolerated dose (MTD), followed by DAUrd treatment, failed to produce a therapeutic gain. We also studied whether non-toxic doses of DAUrd (15-250 mg/kg i.p. at h 0 and 6 on days 4 and 8) could modulate the antileukemic activity of
palmO-ara-C (7.5-120 mg/kg i.p. at h 3 on days 4 and 8). The addition of DAUrd produced a modest (but statistically significant)
prolongation of life span and a further 2-log10 reduction in
tumor burden compared to the same dose of
palmO-ara-C alone, and resulted in long-term survivors in five of 30 treated animals. Two-dimensional dose-response analysis of the survival data indicated a positive drug interaction (p less than or equal to 0.01) when the dosage of DAUrd was modeled to reflect an apparent threshold effect.
Cyclopentenyl cytosine (
CPE-C; 0.625-2.5 mg/kg i.p. at h 0 and 6 on days 4 and 8), a more potent inhibitor of
CTP synthetase, was also given with
palmO-ara-C. This combination resulted in an additional 2-6 log10 units of cell kill and occasional long-term survivors at
palmO-ara-C dosages that alone resulted in no more than 2 log10 units of cell kill and no long-term survivors. However, DAUrd and
CPE-C given with
palmO-ara-C increased host toxicity, compromising the tolerable dose of
palmO-ara-C. Single-agent
palmO-ara-C given at its MTD produced a similar reduction in
tumor burden and increase in life span compared to the highest
palmO-ara-C dose that could be given in combination with either modulator.