Reversal of Resistance to Methotrexate in L1210 Murine Leukemia by Uracil

BDF₁ mice bearing L1210 leukemia, when treated with a regimen of uracil and methotrexate, show an increase in survival time greater than when treated with methotrexate alone. The uracil and methotrexate regimen also delays the development of methotrexate resistance as L1210 leukemia is transferred with therapy through multiple generations of mice. When uracil is applied to multiple generations of mice bearing tumor resistant to methotrexate, there is a return to sensitivity to methotrexate. It is also noted that uracil blocks the responsiveness of L1210 leukemia to 6-mercaptopurine.

The responsiveness of these tumor lines to the addition of uracil in their regimens was monitored by in vitro tritiated thymidine incorporation into DNA and by dihydrofolate reductase activities. These data, when integrated with survival time data, suggest that in part, the reported results are mediated by a uracil-induced reduction in the availability of dihydrofolate reductase and phosphoribosylpyrophosphate.