Comparison of in vitro and in vivo effects of thymidine on L1210 leukemia in mice.

Previous investigators have shown that L1210 leukemia in vitro growth can be inhibited by thymidine (dThd) by exposure for 24 hours of dThd concentrations as low as 0.1 mM. These experiments were conducted in an attempt to determine why dThd, although effective as a cytostatic agent against L1210 in vitro, is ineffective against L1210 in (BALB/c X DBA/2)F1 (CD2F1) mice. Systemic variations of dThd concentration and exposure times were examined in both a growth-inhibition assay and a soft agar cloning assay in vitro. The growth of cells exposed to 0.1 - 1.0 mM dThd for 15 hours was inhibited dramatically during exposure, but growth recovered to control rate rapidly when dThd was washed off the cells. With 96 hours of exposure to 1.0 mM dThd, growth rate did not return to control rate up to 120 hours after washing. Cloning efficiency was reduced to less than 1% of control by prior 96-hour exposure of L1210 cells to more than 0.5 mM dThd. Concentrations of deoxycytidine (dCyd) of 1.0 microM partially reversed cytotoxicity caused by dThd greater than 0.1 mM, and 10 microM dCyd completely reversed this cytotoxicity. In vivo plasma dThd concentrations during ip injections of 3,600 mg dThd/kg body weight every 8 hours for 4 days (approximately lethal dose for 10% of animals treated) ranged from 10 to 0.1 mM, but these concentrations were ineffective in prolonging survival time of L1210-bearing mice. Plasma concentrations of dCyd prior to dThd exposure were less than 1.0 microM. Following injection of dThd (3,600 mg/kg body wt), plasma dCyd was 2.8 +/- 0.5 microM (normal mice) and 6.1 +/- 0.5 microM (L1210-bearing mice). Thus the rise of dCyd in plasma following dThd administration in vivo prevented the cytotoxicity of dThd seen in vitro from being manifested in vivo in CD2F1 mice.