Effect of Thymidine on the Survival of Mice with EL4 Tumors¹

The effect of thymidine (dThd) on the growth of EL4 thymoma tumors in syngeneic C57BL/6 mice was determined. In vitro, EL4 cells are approximately 10-fold more sensitive to dThd than are many other tumor lines, and they are 100-fold more sensitive than are normal cells; dThd (2.5 to 5 µg/ml) were cytostatic, and dThd (12.5 to 25 µg/ml) cytotoxic to EL4 cells. The half-life of dThd in mouse serum was approximately 60 min, so that 20-g mice given injections with 24 mg dThd at 4-hr intervals during the day and with 30 mg dThd before an 8-hr interval overnight were estimated to maintain systemic concentrations of dThd greater than 25 µg/g. Groups of 10 mice were given 2.2 × 10⁷ or 2.4 × 10⁴ EL4 cells i.p. and then treated with 0.86% NaCl or dThd on the 4- and 8-hr regimen. The mean death times of the NaCl- and dThd-treated mice were 9.9 or 16.4 days and 17.7 or 23.1 days, respectively. The 7-day differences between the death times of NaCl- and dThd-treated mice were significant to p < 0.0001, and the 7-day delay in death time was equivalent to that expected from a 3-log reduction in viable EL4 cells. The mean death time of 10 NaCl-treated mice given 2 × 10² cells was 23.9 days, and the death time for 7 of 10 dThd-treated mice was 31.4 days. Three dThd-treated mice given 2 × 10² cells survived until sacrificed at 60 days. The data show that although some sensitive cells may escape inhibition and replicate under the injection regimen used, dThd is cytotoxic to sensitive EL4 cells in vivo. The data suggest that dThd might be a useful chemotherapeutic agent for tumors that have the same level of sensitivity as EL4.