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.
Bowen
D
D
Department of Pharmacology, Howard University College of Medicine, Washington, D.C. 20059, USA.
Johnson
D H
DH
Southerland
W M
WM
Hughes
D E
DE
Hawkins
M
M
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D016597:Trimetrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D016597:Trimetrexate