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Growth inhibition of a human tumor cell strain by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine; reversal studies.
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1958
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Complete Growth InhibitionHuman GrowthMolecular BiologyReversal StudiesCell GrowthEpigeneticsTumor BiologyGrowth InhibitionCancer Cell BiologyBiochemical GeneticsAnti-cancer AgentRadiation OncologyHuman MetabolismCancer ResearchBiochemistryMedicineCancer TreatmentEpigenetic RegulationPharmacologyCell BiologyLabeled ThymidineNatural SciencesCellular BiochemistryMetabolismOncologyCancer Growth
Summary The effects of 5-fluorouracil (FU), 5-fluorouradine (FUR), and 5-fluoro-2′-deoxyuridine (FUDR). on the growth of H.Ep. #1 human cell strain in a semisynthetic medium have been studied. FU, FUR, and FUDR produced complete inhibition of growth at 1.0, 0.01, and 0.01 µg/ml., respectively (8 × 10-6, 0.4 × 10-7, and 0.4 × 10-7m). The complete growth inhibition by FUDR at 4 × 10-7m is reversed by an approximately equivalent concentration of thymidine. The extent of reversal is independent of the FUDR concentration over a fivefold variation in the latter. These results strongly support the hypothesis that a block in the pathway leading to DNA-thymine (probably at the “methylation step”) is the principal cause of growth inhibition by FUDR. However, the inability of thymidine to reverse the growth inhibition by FU and FUR suggests that the latter are producing metabolic blocks at sites essential to growth in addition to the “methylation block” suggested for FUDR inhibition. The growth inhibition by FUDR is reversed by deoxyuridine at an approximately 100-fold excess. A fivefold increase in FUDR concentration increased by a corresponding factor the level of deoxyuridine needed for reversal. The inhibition of growth by FU could not be reversed by a 100-fold excess of thymidine, 5-methyldeoxycytidinc, dcoxyuridine, uridine, cytidine, uracil, thymine, and cytosine. The specific activity of the nucleic acid pyrimidines of H.Ep. #1 cells grown in the presence of FUDR plus thymidine (as reverser) was compared with cells grown in the presence of an equal concentration of thymidine alone. With labeled orotic acid, a significant depression in the specific activity of DNA-thymine was observed in the presence of FUDR, with relatively little effect on the other nucleic acid pyrimidines. With labeled thymidine, the specific activity of the DNA-thymine was increased by a factor of two to four in the presence of FUDR. These results demonstrate an enhanced utilization of exogenous thymidine under conditions in which the de novo pathway to DNA-thymine is blocked by FUDR.