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

Buddy Ullman, H. George Mandel, James L. Day, Wolfgang Sadee, Jonathan Maybaum

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

The mouse T-lymphoma (S-49) cell line is useful for individually studying RNA-and DNA-directed effects of 5-fluoropy-rimidines. 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 (thy-midylate 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 G1phase 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 G1where RNA-directed toxicity is expressed, which may account for the augmentation of FUra toxicity by thymidine as reported in othar systems.

Original languageEnglish (US)
Pages (from-to)4209-4215
Number of pages7
JournalCancer Research
Volume40
Issue number11
StatePublished - Nov 1 1980

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Regulation of RNA-and DNA-directed Actions of 5-Fluoropyrimidines in Mouse T-Lymphoma (S-49) Cells'. Together they form a unique fingerprint.

  • Cite this

    Ullman, B., Mandel, H. G., Day, J. L., Sadee, W., & Maybaum, J. (1980). Regulation of RNA-and DNA-directed Actions of 5-Fluoropyrimidines in Mouse T-Lymphoma (S-49) Cells. Cancer Research, 40(11), 4209-4215.