Schedule-dependent cytotoxicity of 5-fluorouracil and cyclophosphamide in experimental cancer chemotherapy

The effect of drug scheduling of 5-fluorouracil and cyclophosphamide was investigated in L1210 leukaemia, the Lewis lung carcinoma and the mouse C22LR osteosarcoma. The optimum antitumour schedule was found to be that in which the drugs were given simultaneously. In the treatment of L1210 and the Lewis lung carcinoma, drug synergism was observed when the two agents were administered simultaneously. A similar trend was less pronounced for the osteosarcoma. The most cytotoxic schedule for bone marrow stem cells was cyclophosphamide followed by 5-fluorouracil. As a consequence of this differential effect, the best tolerated and generally also the most effective antitumour schedule was the simultaneous administration of the two drugs. These experimental data should lead to critical testing of clinically used multi-drug combinations, e.g., Bonadonna's CMF regimen in patients with metastatic mammary carcinoma.