Interaction of 5'-deoxy-5-fluorouridine and methotrexate. A basis for reduced methotrexate toxicity.

Methotrexate (MTX) toxicity is reduced significantly by a non-toxic dose of 5'-deoxy-5-fluorouridine (5'dFUr). Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), ileal tissue, and body weight were used as parameters to assess toxicity. MTX treatment alone resulted in: (a) a reduction of body weight; (b) significantly morphological changes in ileal tissue; and (c) a marked decrease in the hematopoietic parameters. Sequential treatment with MTX followed by 5'dFUr resulted in reversal of MTX depression of animal body weight and ileal tissue necrosis, and partial reversal in MTX toxicity to the hematopoietic system. Also, for all parameters studied, there were no significant differences between scheduling of MTX after a priming dose of 5'dFUr, 5'dFUr alone, and control. Hence, this study suggests that 5'dFUr is a pharmacological antidote for MTX toxicity, and, therefore, 5'dFUr in combination with MTX may provide a basis whereby more intense and effective MTX therapy may be given.