Significance of variation in serum thymidine concentration for the marrow toxicity of methotrexate

Thymidine (dThd) concentrations have been measured in the sera of normal subjects and solid tumor cancer patients by means of a sensitive high-pressure liquid chromatographic assay to determine whether natural and methotrexate (MTX)-induced fluctuations were large enough to alter the toxicity of MTX to marrow. The mean concentration in normal subjects with measurable levels was 1.3 X 10(-7) M (range less than 4 X 10(-8) to 6 X 10(-7) M). In cancer patients it was 2.0 X 10(-7) M (range less than 4 X 10(-8) to 8.7 X 10(-7)), and in malignant effusions 1.2 X 10(-7) M (range less than 4 X 10(-8) to 2.2 X 10(-7) M). The wide range of variation in random samples was also found when multiple samples were obtained from the same patient during a 24-h period where dThd concentration varied from a minimum of two- to greater than six-fold. Treatment with MTX 3 mg/m2 caused an average 59% reduction in serum dThd during the first 24 h after injection during nine courses of therapy. dThd was tested for its ability to modulate the toxicity of MTX to human granulocate colony-forming units in culture across the concentration range found in vivo: changes in dThd concentration equivalent to normal fluctuations in vivo altered colony survival by 31% to greater than 72%. A reduction in culture dThd equivalent to that produced in vivo by high-dose TMX increased colony kill by 25%. The results indicate that in vivo variations in serum dThd are in an appropriate range and of a sufficient magnitude to alter the toxicity of MTX to marrow, and they demonstrate that MTX can modulate its own toxicity by reducing serum dThd.