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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.
G B FitzGerald, and
J Ratliff, and
M M Wick
July 1985,
Biochemical pharmacology,
G B FitzGerald, and
J Ratliff, and
M M Wick
January 1982,
Biochimica et biophysica acta,
G B FitzGerald, and
J Ratliff, and
M M Wick
January 1993,
Advances in experimental medicine and biology,
G B FitzGerald, and
J Ratliff, and
M M Wick
October 2004,
Nucleosides, nucleotides & nucleic acids,
G B FitzGerald, and
J Ratliff, and
M M Wick
April 1982,
Analytical biochemistry,
G B FitzGerald, and
J Ratliff, and
M M Wick
May 1987,
Biochemical pharmacology,
G B FitzGerald, and
J Ratliff, and
M M Wick
January 1990,
Neoplasma,
G B FitzGerald, and
J Ratliff, and
M M Wick
January 1989,
The International journal of biochemistry,
G B FitzGerald, and
J Ratliff, and
M M Wick
July 1980,
Biochimica et biophysica acta,
G B FitzGerald, and
J Ratliff, and
M M Wick
March 1967,
Cancer research,
