REGULATION OF RNA-DIRECTED AND DNA-DIRECTED ACTIONS OF 5-FLUOROPYRIMIDINES IN MOUSE T-LYMPHOMA (S-49) CELLS

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (11) , 4209-4215
Abstract
The mouse T-lymphoma (S-49) cell line is useful for studying RNA- and DNA-directed effects of [the antineoplastic] 5-fluoropyrimidines. 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 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 h both by the accumulation of intracellular dUMP 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. DNA-directed toxicity prevents cells 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.