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Mechanism of Growth Inhibition by Methotrexate¹

Department of Medical Biophysics, University of Toronto, and the Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9

The effect of methotrexate on the growth of Chinese hamster cells was examined under a variety of conditions. The experiments suggest that the important biological effects of methotrexate are the result of direct inhibition of thymidylate synthetase and one or both of the folate-dependent enzymes involved in purine biosynthesis. In addition, analysis of the distribution of intracellular folate derivatives following methotrexate treatment gives no indication of accumulation of dihydrofolate, an accumulation that would be expected if inhibition of dihydrofolate reductase were the principal site of methotrexate action.

¹ This work was supported by grants from the Medical Research Council of Canada, from the National Cancer Institute of Canada, and from Contract NIH-NCI-72-2051(c) of the NIH.

² Present address: Department of Zoology, South Parks Road, Oxford, England, OX1 3PS.

Received 1/ 9/74. Accepted 11/ 5/74.