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Cell Killing Studies on the Mode of Action of Methotrexate on L-cells in Vitro¹

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

Studies were carried out on L-cells in vitro realting the various Methotrexate (MTX)-induced perturbations of cellular metabolism to cell killing by the drug. In the tissue culture system used in these investigations, the inhibitory action of MTX could be completely reversed by the addition of thymidine and deoxyadenosine to the culture medium, indicating that all of the MTX-induced effects on cell proliferation and viability were due to the depletion of thymidylate and purines brought about by MTX disruption of folic acid metabolism. This permitted the resolution of the effects of these two inhibitions on cell killing. Results indicate clearly that cell killing results from the inhibition of thymidylate synthesis while the concurrent inhibition of purine synthesis tends to prevent efficient cell killing. Furthermore, it was shown that cells whose proliferation was inhibited prior to exposure to MTX, either by lack of essential amino acids in the medium or by their having reached a stationary growth phase, were resistant to the cell killing action of the drug. The significance of these results for chemotherapy is discussed.

¹ Supported in part by the National Cancer Institute of Canada and by a grant. Number CA 06229, from the NIH (U. S.).

² Fellow of the National Cancer Institute of Canada.

³ Present address: Wistar Institute, 36th and Spruce Street, Philadelphia, Pennsylvania 19104.

Received 8/ 8/69. Accepted 11/16/68.