Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines

Jae Gahb Park, Jerry M. Collins, Adi F. Gazdar, Carmen J. Allegra, Seth M. Steinberg, Raymond F. Greene, Barnett S. Kramer

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (5-FU) by stabilizing the 5-fluoro-2′-deoxyuridine-5′-monophosphate-thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay, we tested the effects of 5-FU and 5-fluoro-2′-deoxyuridine (FdUrd) with and without leucovorin (LV) on a panel of 11 human colorectal carcinoma cell lines. The effect of LV on 5-FU and FdUrd was quantitatively similar. A clinically achievable level of LV (20 μM) increased the cytotoxicity in all three replicate experiments in 10 of the 11 cell lines (P < .05, binomial test). LV alone at a concentration of 20 μM had no effect on cell survival. In three cell lines, 50% inhibition of growth occurred at a clinically achievable area under the curve of 5-FU alone. With the addition of LV, one additional cell line showed 50% growth inhibition at a clinically achievable level of 5-EU. Hence large clinical trials may be necessary to detect a significant improvement in survival as a result of adding LV to the fluorinated pyrimidines. [J Nail Cancer Inst 188;80:1560-1564]

Original languageEnglish (US)
Pages (from-to)1560-1564
Number of pages5
JournalJournal of the National Cancer Institute
Volume80
Issue number19
DOIs
StatePublished - Jul 7 1988

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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