Positive interaction between 5-FU and FdUMP[10] in the inhibition of human colorectal tumor cell proliferation.
Interaction between 5-fluorouracil (5-FU) and FdUMP[10], a novel pro-drug formulation of the thymidylate synthase (TS) inhibitory nucleotide 5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP), was investigated to evaluate the feasibility of using these two forms of fluorinated pyrimidine in combination chemotherapy regimens. 5-FU and FdUMP[10] are expected to differ in their relative intracellular distribution of active metabolites, and their combined administration may result in either a positive or a negative interactive effect. The dose-response behaviors of 5-FU and FdUMP[10] toward H630 and H630-10 (human colorectal tumor) cells were first investigated separately. Effects on cell viability were measured using an assay for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), while cytotoxicity and apoptosis were investigated using clonogenic and TUNEL assays, respectively. Exposure of H630 cells to concentrations of FdUMP[10] insufficient to inhibit cell proliferation as a single agent markedly increased the cytotoxicity of 5-FU. The results indicate that 5-FU and FdUMP[10] interact in a positive manner, and that combining these two forms of fluorinated pyrimidine may be clinically beneficial.
Liu
J
J
Eppley Institute, and Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Kolath
J
J
Anderson
J
J
Kolar
C
C
Lawson
T A
TA
Talmadge
J
J
Gmeiner
W H
WH
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004357:Drug Synergism; D005468:Fluorodeoxyuridylate / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D011355:Prodrugs / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005468:Fluorodeoxyuridylate; D005472:Fluorouracil