Comparison of the in vitro cytotoxicity (L1210) of 5-aza-2'-deoxycytidine with its therapeutic and toxic effects in mice.

The in vitro and in vivo cytotoxic effects of 5-aza-2'-deoxycytidine (DAC) on L1210 leukemia are reported and related to the pharmacokinetics of DAC in CDF mice. L1210-bearing mice (1 X 10(4) cells, i.v.) given DAC i.v. (6.5-225 mg/kg) on day 3 showed a 50-212% increase in lifespan (ILS), with an estimated 3-6 log cell kill of L1210. Optimal effects with late treatment were obtained when DAC was given either on a multiple-dose regimen (10 mg/kg i.v., q 3 hr X 4, day 3 or 5) or by a constant s.c. infusion (2.0 mg/kg/hr X 12 hr, day 3), ILS 328-414%. Following 10 or 100 mg/kg i.v., plasma DAC declined in a triexponential manner with an intermediate elimination t 1/2 of 31 min. Urinary excretion accounted for 28.5% of DAC plasma clearance. When L1210 cells were exposed to DAC in vitro (0.5-100 micrograms/ml for 24-120 hr) a maximum 3-4 log cell kill was obtained. Both in vivo and in vitro response to DAC demonstrated the importance of exposure time as a determinant of cell kill. DAC is estimated to be more cytotoxic in vivo than in vitro. The critical cytotoxic concentration of DAC appears to be between 0.5 and 1.0 microgram/ml.