title: Modulation of cytosine arabinoside toxicity by 3-deazauridine in a murine leukemia model.
abstract: 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.
authors.affiliation: Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
authors.forename: J
authors.initials: J
authors.lastname: Plowman
authors.forename: L
authors.initials: L
authors.lastname: Rubinstein
authors.forename: M J
authors.initials: MJ
authors.lastname: Hawkins
authors.forename: S D
authors.initials: SD
authors.lastname: Harrison
mesh_terms: D015092:3-Deazauridine / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012074:Remission Induction; D015996:Survival Rate
chemical_list: D003561:Cytarabine; D015092:3-Deazauridine; D003562:Cytidine; C045911:cyclopentenyl cytosine; C008758:5'-palmitoyl cytarabine