Selectivity in human breast cancer and human bone marrow using trimetrexate in combination with 5-fluorouracil

The growth inhibitory effect of trimetrexate (TMQ) is maintained in MCF-7 b reast cancer but is decreased in Hs 824.T human bone marrow cell by a primi ng- and non-toxic 5-fluorouracil (5-FU) dose. Incubation of MCF-7 breast ce lls with 10 mu M TMQ alone or in combination with 10 M 5-FU (TMA 2h prior t o 5-FU [TMQ/5-FU] or 5-FU 2h prior to TMQ[5-FU/TMQ]) resulted in similar in hibitory effects but dissimilar effects occurred in Hs 824. T bone marrow. In breast cancer, the percentage differences among TMQ and TMQ/5-FU, TMQ an d 5-FU/TMQ, and TMQ/5-FU and 5-FU/TMQ on growth rates, respectively, were 3 .56%, 2.35%, and 1.68%. The percentage differences on growth rates of TMQ a nd TMQ/5-FU, TMQ and 5-FU/TMQ, and TMQ/5-FU and 5-FU/TMQ in bone marrow, re spectively, were 5.76%, 30.03% (significant protection by 5-FU, i.e. the in hibitory effect of 5-FU/TMQ less than or equal to TMQ), and 35.78% (sequenc e dependent). The growth rates of breast cancer and bone marrow cells in th e presence of 5-FU were 96.03 +/- 1.17% and 94.59 +/- 1.15%, respectively, of control rates. These studies suggest that (a)TMQ and 5-FU combinations o n the growth of MCF-7 breast cancer cells are independent of sequence of ad ministration and best related to TMQ and (b) a priming- and non-toxic 5-FU dose protects against TMQ toxicity in human bone marrow while not affecting the maximum inhibitory effect of TMQ in breast cancer.