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

Abstract

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 1.3x10^-7 M (range -8 to 6x10^-7 M). In cancer patients it was 2.0x10^-7 M (range -8 to 8.7x10^-7), and in malignant effusions 1.2x10^-7 M (range 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.