5-Fluorouracil simultaneously maintains methotrexate antineoplastic activity in human breast cancer and protects against methotrexate cytotoxicity in human bone marrow.
High-dose methotrexate (MTX) cytotoxicity is maintained in MCF-7 breast cancer cells but reduced in Hs824.T human bone marrow by a priming and nontoxic 5-fluorouracil (5-FU) dose. When MCF-7 breast or Hs824.T bone marrow cells are incubated with 10 microM 5-FU and 10 microM MTX for 48 h, the growth rates of breast cancer cells were 97.59 +/- 0.97% and 21.81 +/- 3.33% of the control rate, respectively, and the growth rates of bone marrow cells were 90.61 +/- 3.71% and 29.58 +/- 2.99% of the control rate. The combinations of 5-FU 2 h prior to MTX or MTX 2 h prior to 5-FU followed by a 48 h incubation, respectively, gave growth rates of 20.96 +/- 2.44% and 19.86 +/- 2.56% of the control rate for MCF-7 cells. In bone marrow cells, the combinations of 5-FU 2 h prior to MTX or MTX 2 h prior to 5-FU followed by a 48 h incubation, respectively, gave growth rates of 79.66 +/- 7.41% (protection) and 31.39 +/- 1.77% of the control rate. Similar patterns to bone marrow emerges in platelets. These studies suggest that: a) MTX and 5-FU combination on the growth of human MCF-7 breast cancer cells is independent of sequence; and b) a priming-dose of 5-FU will protect bone marrow from MTX cytotoxicity but not breast cancer cells. Therefore, a priming and non-toxic dose of 5-FU and MTX may have maximum antineoplastic activity while at the same time provide protection to the hematopoietic system.
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
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D008727:Methotrexate