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Effect of Intravenous Infusion of 5-Aza-2'-Deoxycytidine on Survival Time of Mice with L1210 Leukemia¹

Department of Pharmacology and Pediatrics, University of Southern California School of Medicine [R. L. M.], and Division of Hematology-Oncology, Childrens Hospital of Los Angeles [R. L. M., F. A. G.], Los Angeles, California 90027

The effect of i.v. infusions of 5-aza-2'-deoxycytidine (5-aza-dCyd) on the survival time of BALB/c x DBA/2 F1 (hereafter called CD2F₁) mice with L1210 leukemia was investigated. The mice were inoculated i.v. with 5 x 10⁴ L1210 leukemic cells 3 days before start of chemotherapy. There was a good correlation between the number of L1210 leukemic cells inoculated i.v. and the survival time of the CD2F₁ mice. The minimal effective dose of 5-aza-dCyd that produced a significant increase (20%) in life span for a 1.0-hr i.v. infusion was about 0.4 mg/kg. When 5-aza-dCyd was infused at a flow rate of 0.6 mg/kg/hr, the survival time of the leukemic mice increased with the duration of the infusion. When this infusion of 5-aza-dCyd was extended to 4.0 hr, it produced 58% increase in life span or an estimated leukemic cell kill of greater than 99%, suggesting that the in vivo cytotoxic action of this S-phase-specific agent was not self-limiting.

The elimination half-life of 5-aza-dCyd and/or its cytotoxic equivalent in nonleukemic CD2F₁ mice as determined by an in vitro cytotoxicity bioassay was estimated to be about 40 min. Pharmacokinetic analysis was performed to estimate the average plasma concentration of 5-aza-dCyd during the i.v. infusion and to correlate it with the antileukemic activity. The minimal effective dose of 5-aza-dCyd for an 8.0-hr i.v. infusion was about 0.4 mg/kg and produced an estimated average drug plasma concentration of 0.06 µg/ml. This concentration was in the same range as that required to produce 80% kill of L1210 leukemic cells growing in tissue culture, indicating that there was a good correlation between the in vivo and in vitro antileukemic activity of 5-aza-dCyd. An 8.0-hr i.v. infusion of 5-aza-dCyd at a dose of 4.4 mg/kg produced an estimated average drug plasma concentration of 0.6 µg/ml and greater than 150% increase in life span, a potent antileukemic effect. The doses lethal to 10 and 50% of the mice of 5-aza-dCyd for 8-hr infusion in nonleukemic mice were 25 and 54 mg/kg, respectively, indicating that this nucleoside analog has a high therapeutic index against L1210 leukemia in CD2F₁ mice.

¹ This investigation was supported by USPHS Grant CA19696 from the National Cancer Institute.

² Present address: Center de Recherche Pediatrique, Hospital Sainte-Justine, 3175, Chemin Côte Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada. To whom requests for reprints should be addressed.

Received 3/17/77. Accepted 5/22/78.