Toxicity, pathological effects, and antineoplastic activity of a non-toxic dose of 5-fluorouracil in combination with methotrexate.

The survival time of CF-1 mice bearing Ehrlich ascites tumor cells was increased significantly by i.p. administration of a non-toxic dose of 5-fluorouracil (25 mg/kg) followed by methotrexate (40 mg/kg). The effects of 5-fluorouracil (FU) and methotrexate (MTX), singly and in combination, were examined on the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), body weight, and the crypt of Liberkühn to assess toxicity, and on survival of tumor-bearing animals to assess antineoplastic activity. Sequential treatment with a non-toxic dose of FU followed by MTX for 3 consecutive days produced no significant adverse effect. MTX alone and the scheduling of FU after a priming dose of MTX resulted in: (a) a marked decrease in the hematopoietic parameters; (b) significant morphological changes in ileal tissue; and (c) a reduction in body weight. The survival of tumor-bearing animals treated with FU alone and FU 2 hours before MTX was 124% and 139% greater than control, respectively. The survival rate of animals treated with MTX alone was less than that of untreated tumor animals. This study suggests the feasibility of designing FU and MTX regimens that will have little or no systemic toxicity while maintaining antineoplastic activity.