Differentially potentiating effects by dipyridamole on cytotoxicity of 5-fluorouracil against three human maxillary cancer cell lines derived from a single tumor.
Dipyridamole (DPM), an inhibitor of nucleoside transport, is a unique potentiator of 5-fluorouracil (5-FU). We examined the combined effects of DPM and 5-FU on three cell lines (IMC-2, IMC-3, IMC-4) derived from a single tumor of a patient with maxillary cancer. DPM at 1.0-2.0 microM potentiated the cytocidal action of 5-FU > 20-fold against IMC-2 cells, while DPM at 10-20 microM potentiated the action of 5-FU against IMC-3 cells by 2-fold and against IMC-4 cells by approximately 4-fold. We examined why DPM differentially potentiated 5-FU against the three cell lines. The three maxillary cell lines showed heterogeneous sensitivities to the combination of 5-FU and DPM. We compared intracellular metabolism of 5-FU in IMC-2, IMC-3 and IMC-4 cells by HPLC. Determination of 5-FU metabolites demonstrated that cellular contents of 5-fluorodeoxyuridine monophosphate (FdUMP) were 104.66, 15.35 and 61.5 fmol/10(6) cells in IMC-2, IMC-3 and IMC-4 cells, respectively, in the presence of 10 microM DPM when the three cell lines had similar levels (0.21-0.33 fmol/10(6) cells) of FdUMP in the absence of DPM. By contrast, cellular levels of 5-FU and 5-fluorouridine triphosphate (FUTP) were not appreciably changed by DPM in three cell lines. The cellular level of thymidylate synthase mRNA in IMC-2 cells was found to be about one-fifth of that in IMC-3 and IMC-4 cells. The differential effects of DPM on the potentiation of 5-FU cytotoxicity might be closely related to the cellular levels of FdUMP and its target enzyme, thymidylate synthase in three human maxillary cancer cell lines.
Sato
S
S
Department of Biochemistry, Oita Medical University, Japan.
Kohno
K
K
Hidaka
K
K
Hisatsugu
T
T
Kuwano
M
M
Komiyama
S
S
D002470:Cell Survival / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008441:Maxillary Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism
D005468:Fluorodeoxyuridylate; C025635:5-fluorouridine 5'-triphosphate; D004176:Dipyridamole; D005472:Fluorouracil; D014544:Uridine Triphosphate