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Molecular Pharmacology, Vol 5, 318-332, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

Studies Relating to the Mode of Action of Methotrexate

III. Inhibition of Thymidylate Synthetase in Tissue Culture Cells and in Cell-Free Systems

J. BORSA 1 and G. F. WHITMORE 1

1 Department of Medical Biophysics, University of Toronto, and Ontario Cancer Institute, Toronto 5, Ontario, Canada

The effect of methotrexate on thymidylate synthesis in mammalian cells in vitro has been studied by using the incorporation of deoxyuridine-6-3H into DNA as an assay for thymidylate synthesis. The results are consistent with the interpretation that inside the living cell methotrexate can inhibit thymidylate synthetase directly. In studies on the effects of this drug on thymidylate synthetase activity in cell-free preparations, using both mammalian and bacterial enzyme sources, inhibition of the synthetase was observed. The inhibition yielded Lineweaver-Burk plots that were uncompetitive with respect to deoxyuridylic acid and competitive with respect to tetrahydrofolate. Values of 1.4 (±0.1) x 10-5 M and 4.3 (±1.2) x 10-6 M were measured for Ki,intercept and Ki, slope, respectively. The possible significance of these findings is discussed.

Note:
ACKNOWLEDGMENTS We thank Drs. W. R. Bruce and J. E. Till for helpful discussions.

Submitted on February 24, 1969






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