Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells.
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 hve 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.
D000818:Animals; D002453:Cell Cycle; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005467:Floxuridine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D011742:Pyrimidine Nucleotides / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D004273:DNA, Neoplasm; D011742:Pyrimidine Nucleotides; D011743:Pyrimidines; D012334:RNA, Neoplasm; D005467:Floxuridine; C029269:5-fluoropyrimidine; D005472:Fluorouracil; D013936:Thymidine