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Thymidylate Synthetase Activity in the Novikoff Hepatoma¹

Section of Biochemistry and Biophysics, Biological Sciences Group, University of Connecticut, Storrs, Connecticut 06268

The mechanism by which injected methotrexate increases thymidylate synthetase activity in the Novikoff hepatoma has been studied. Folic acid injection causes a similar increase in enzyme activity in hepatoma after 16 hr but the action of folic acid and methotrexate is not additive.

The increase in activity of thymidine 5'-phosphate synthetase in the hepatoma caused by methotrexate is not affected by actinomycin D, but is inhibited 50% by puromycin and 100% by cycloheximide.

High-speed supernatant fraction prepared from hepatoma of animals treated with methotrexate has, initially, one-half the specific thymidine 5'-phosphate synthetase activity of untreated controls. Upon addition of increasing amounts of tetrahydrofolate, the specific enzyme activity in the supernatant fraction from the methotrexate-treated animals rises to double that of the controls.

Puromycin added to homogenates of Novikoff hepatoma consistently increases enzyme activity by approximately 20%.

One hypothesis consistent with these results and results reported by others is presented.

¹ This work was supported by Research Grant CA-08384 from the National Cancer Institute. Portions of this work have been presented at the Sixty-Second Meeting of the American Society of Biological Chemists, San Francisco, 1971.

² Abstracted from a thesis presented in partial fulfillment of the requirements for the Ph.D. degree, University of Connecticut, 1973 (16).

³ Recipient of Career Fellowship Award RC 31-63 from the National Cancer Institute.

Received 11/ 7/75. Accepted 8/11/76.