Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells

Buddy Ullman, B. Ullman, H. G. Mandel, J. L. Day, W. Sadee

Research output: Contribution to journalArticle

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Abstract

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 effects on pyrimidine nucelotide 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 G 1 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 G 1 where RNA-directed toxicity is expressed, which may account for the augmentation of FUra toxicity by thymidine as reported in other systems.

Original languageEnglish (US)
Pages (from-to)4209-4215
Number of pages7
JournalCancer Research
Volume40
Issue number11
StatePublished - 1980

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Lymphoma
RNA
Fluorouracil
DNA
Floxuridine
Thymidylate Synthase
Deoxyuridine
S Phase
Thymidine
Pyrimidine Nucleotides
Growth
5-fluoropyrimidine
Cell Cycle
Cell Culture Techniques
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ullman, B., Ullman, B., Mandel, H. G., Day, J. L., & Sadee, W. (1980). Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. Cancer Research, 40(11), 4209-4215.

Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. / Ullman, Buddy; Ullman, B.; Mandel, H. G.; Day, J. L.; Sadee, W.

In: Cancer Research, Vol. 40, No. 11, 1980, p. 4209-4215.

Research output: Contribution to journalArticle

Ullman, B, Ullman, B, Mandel, HG, Day, JL & Sadee, W 1980, 'Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells', Cancer Research, vol. 40, no. 11, pp. 4209-4215.
Ullman, Buddy ; Ullman, B. ; Mandel, H. G. ; Day, J. L. ; Sadee, W. / Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. In: Cancer Research. 1980 ; Vol. 40, No. 11. pp. 4209-4215.
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