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

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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.