Inhibition of thymidylate synthase in intact L1210 cells by ara-C, daunomycin, hydroxyurea and 3,4-dihydroxybenzylamine.
The use of an in situ assay for thymidylate synthase has shown that a variety of clinically important drugs, including arabinofuranosylcytosine, hydroxyurea, and daunomycin, inhibit thymidylate synthase in intact cells. In contrast to the inhibition observed with 5-fluorodeoxyuridine, inhibition occurs by an indirect mechanism, is delayed in onset, and is incomplete. Inhibition occurred at concentrations that corresponded to those that inhibit DNA synthesis, suggesting that this phenomenon might contribute to the biological action of these agents. Since the inhibition of thymidylate synthase by this indirect mechanism appears to be a general property of drugs that inhibit DNA synthesis, our findings may have important implications for the mechanism of killing of tumor cells, as well as the rationale for combination regimens.
FitzGerald
G B
GB
Division of Medicine, Dana-Farber Cancer Institute, Boston, MA 02115.
Ratliff
J
J
Wick
M M
MM
D000818:Animals; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D003630:Daunorubicin / Q000494:pharmacology*; D003857:Deoxyuridine / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005467:Floxuridine / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology*; D007700:Kinetics; D007939:Leukemia L1210 / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D005467:Floxuridine; D003561:Cytarabine; C022133:3,4-dihydroxybenzylamine; D004247:DNA; D013940:Thymidylate Synthase; D004298:Dopamine; D003857:Deoxyuridine; D006918:Hydroxyurea; D008727:Methotrexate; D003630:Daunorubicin