Potentiation of the antitumor activity of methotrexate by concurrent infusion of thymidine.

The effects of normal metaboliteson the toxicity and antitumor activity of methotrexate against leukemia L1210 in DBA/2J mice were evaluated by a systemthat allows for long-term continuous i.v. infusion of unrestrained mice. In normal female DBA/2J mice, the infusion of methotrexatealone for 48 hr produceda 50% lethal dose of 6 mg/kg/day. Coadministrationof thymidine(5 g/kg/ day) and methotrexate,followedby an additional48 hr of thymidine alone, dramatically reduced toxicity, resulting in a 50% lethal dose of about 45 mg/kg/day. A higher concentration of thymidine (18 g/kg/day), which was only marginally toxic alone, was even more effective and reducedthe toxicityof methotrexatemorethan35-fold. AgainstleukemiaL1210in female DBA/2Jmice, a 48-hr infusionof methotrexateproduceda 33% increase in life spanat the optimumdoseof 1 mg/kg/day. The additionof thymidine (5 g/kg/day) to the methotrexate for 48 hr potentlated antitumor activity and resulted In a maximum @ 68% Increase in life span with methotrexate at 4 mg/kg/ day. At higherconcentrationsof methotrexate,two addi tional days of thymidine infusion were required for pre vention of toxicity while maintainingantitumoractivity. Maximumtherapeuticselectivityand a 125%Increase in life span were obtained with methotrexate at 16 mg/kg! day, infusedfor 48 hr concurrentlywith thymidineat 5 g! kg/day for 96 hr. A higherconcentrationof thymidine(15 g/kg!day), although affording a greater than 35-fold re ductionin toxicity,also preventedantitumoractivity. The infusionof inosbnealone or in combinationwith thymidine blocked both the toxicity and antitumor activity of methotrexate.These resultsIndicatethat the Increase in the therapeutic selectivityachieved with the simulta neous infusion of methotrexate and thymidine may result from a complex modulation of cellular metabolism rather than simple end product reversal by the provision of thymidylate.