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 breast cancer but is decreased in Hs 824.T human bone marrow cells by a priming- and non-toxic 5-fluorouracil (5-FU) dose. Incubation of MCF-7 breast cells with 10 microM TMQ alone or in combination with 10 M 5-FU (TMQ 2 h prior to 5-FU [TMQ/5-FU] or 5-FU 2 h prior to TMQ[5-FU/TMQ]) resulted in similar inhibitory effects but dissimilar effects occurred in Hs 824.T bone marrow. In breast cancer, the percentage differences among TMQ and TMQ/5-FU, TMQ and 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 and TMQ/5-FU, TMQ and 5-FU/TMQ, and TMQ/5-FU and 5-FU/TMQ in bone marrow, respectively, were 5.76%, 30.03% (significant protection by 5-FU, i.e. the inhibitory effect of 5-FU/TMQ < or = TMQ), and 35.78% (sequence dependent). The growth rates of breast cancer and bone marrow cells in the 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 on the growth of MCF-7 breast cancer cells are independent of sequence of administration 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.