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Regulation of RNA- and DNA-directed Actions of 5-Fluoropyrimidines in Mouse T-Lymphoma (S-49) Cells¹

Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143

The mouse T-lymphoma (S-49) cell line is useful for individually studying RNA- and DNA-directed effects of 5-fluoropyrimidines. On the basis of their metabolic activation, biochemical effects on pyrimidine nucleotide metabolism, and biological toxicity, we have established that incubation of S-49 cells with 5-fluorodeoxyuridine produces only DNA-directed toxicity (thymidylate synthetase inhibition), incubation with 5-fluorouracil (FUra) + thymidine only RNA-directed toxicity, and incubation with FUra alone produces both DNA- and RNA-directed toxicity. The DNA component of 5-fluoropyrimidine toxicity causes immediate growth inhibition of asynchronous S-49 cell cultures, which is self-limited within 12 hr both by the accumulation of intracellular deoxyuridine 5'-monophosphate competing for thymidylate synthetase binding and by the excretion of deoxyuridine into the cell medium which competes with 5-fluorodeoxyuridine uptake. The RNA-directed component causes growth inhibition and cell kill after a delay of 1 doubling time in asynchronous cultures. Studies with cells synchronized by centrifugal elutriation indicate that the RNA-directed FUra effects are expressed only in the G₁ phase of the cell cycle and cause rapid cell lysis, while the DNA-directed component is specific to the S phase. Experiments using continuous exposure of synchronized cells to FUra alone demonstrate that the activities of the RNA- and DNA-directed components interact with each other. Specifically, DNA-directed toxicity arrests cells in S phase, preventing them from progressing into G₁ where RNA-directed toxicity is expressed, which may account for the augmentation of FUra toxicity by thymidine as reported in other systems.

¹ Supported by NIH Grant GM16496. Work was performed in the Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, Calif.

² To whom requests for reprints should be addressed, at Department of Pharmacology, George Washington University Medical Center, 2300 Eye Street, N. W., Washington, D. C. 20037.

³ Present address: Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, Calif.

⁴ Present address: Department of Pharmacology, School of Medicine, George Washington University, Washington, D. C., American Cancer Society Scholar in Cancer Research during sabbatical leave at University of California, San Francisco, Calif.

⁵ Present address: School of Pharmacy, Florida A & M University, Tallahassee, Fla.

Received 3/10/80. Accepted 8/11/80.

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