Potentiation of the antitumor activity of methotrexate by concurrent infusion of thymidine
Semon, J.H.; Grindey, G.B.
Cancer Research 38(9): 2905-2911
1978
ISSN/ISBN: 0008-5472 PMID: 679199 Document Number: 131666
The effects of normal metabolites on the toxicity and antitumor activity of methotrexate against leukemia L1210 in DBA/2J mice were evaluated by a system that allows for long-term continuous i.v. infusion of unrestrained mice. In normal female DBA/2J mice, the infusion of methotrexate alone for 48 h produced an LD50 of 6 mg/kg per day. Coadministration of thymidine (5 g/kg per day) and methotrexate, followed by an additional 48 h of thymidine alone, dramatically reduced toxicity, resulting in an LD50 of about 45 mg/kg per day. A higher concentration of thymidine (18 g/kg per day), which was only marginally toxic alone, was even more effective and reduced the toxicity of methotrexate more than 35-fold. Against leukemia L1210 in female DBA-2J mice, a 48-h infusion of methotrexate produced a 33% increase in life span at the optimum dose of 1 mg/kg per day. The addition of thymidine (5 g/kg per day) to the methotrexate for 48 h potentiated antitumor activity and resulted in a maximum 68% increase in life span with methotrexate at 4 mg/kg per day. At higher concentrations of methotrexate, 2 additional days of thymidine infusion were required for prevention of toxicity while maintaining antitumor activity. Maximum therapeutic selectivity and a 125% increase in life span were obtained with methotrexate at 16 mg/kg per day, infused for 48 h concurrently with thymidine at 5 g/kg per day for 96 h. A higher concentration of thymidine (15 g/kg per day), although affording a greater than 35-fold reduction in toxicity, also prevented antitumor activity. The infusion of inosine alone or in combination with thymidine blocked the toxicity and antitumor activity of methotrexate. The increase in the therapeutic selectivity achieved with the simultaneous 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.