Corpus ID: 5801175

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

@article{Semon1978PotentiationOT,
  title={Potentiation of the antitumor activity of methotrexate by concurrent infusion of thymidine.},
  author={J H Semon and Gerald Burr Grindey},
  journal={Cancer research},
  year={1978},
  volume={38 9},
  pages={
          2905-11
        }
}

• J. Semon, G. Grindey
• Published 1 September 1978
• Medicine
• Cancer research

Abstract 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 hr produced a 50% lethal dose of 6 mg/kg/day. Coadministration of thymidine (5 g/kg/day) and methotrexate, followed by an additional 48 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 reduced the toxicity of methotrexate more than 35-fold. Against leukemia L1210 in female DBA/2J mice, a 48-hr infusion of methotrexate produced a 33% increase in life span at the optimum dose of 1 mg/kg/day. The addition of thymidine (5 g/kg/day) to the methotrexate for 48 hr potentiated antitumor activity and resulted in a maximum 68% increase in life span with methotrexate at 4 mg/kg/day. At higher concentrations of methotrexate, two 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/day, infused for 48 hr concurrently with thymidine at 5 g/kg/day for 96 hr. A higher concentration of thymidine (15 g/kg/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 both the toxicity and antitumor activity of methotrexate. These results indicate that the increase in 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.