The CMF-regimen. Toxicity patterns following stepwise combinations of cyclophosphamide, methotrexate and fluorouracil

The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.