Modulation of 5-fluorouracil by 5-ethyl-2'deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities

Csilla Katona, Ferenc Tímár, A. Jeney, Jean L. Fischel, Gerard Milano, Erzsébet Pandi, Judit Kralovánszky

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50 = 194 μM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55%, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.

Original languageEnglish
Pages (from-to)561-567
Number of pages7
JournalAnti-Cancer Drugs
Volume10
Issue number6
Publication statusPublished - 1999

Fingerprint

Dihydrouracil Dehydrogenase (NADP)
Fluorouracil
Cell Line
Thymidylate Synthase
Thymidine Kinase
Pyrimidine Phosphorylases
Proteins
edoxudin
DNA-Directed DNA Polymerase
Inhibitory Concentration 50
Nucleotides

Keywords

  • 5-Ethyl-2'-deoxyuridine
  • 5-Fluorouracil modulation
  • Dihydropyrimidine dehydrogenase

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Katona, C., Tímár, F., Jeney, A., Fischel, J. L., Milano, G., Pandi, E., & Kralovánszky, J. (1999). Modulation of 5-fluorouracil by 5-ethyl-2'deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities. Anti-Cancer Drugs, 10(6), 561-567.

Modulation of 5-fluorouracil by 5-ethyl-2'deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities. / Katona, Csilla; Tímár, Ferenc; Jeney, A.; Fischel, Jean L.; Milano, Gerard; Pandi, Erzsébet; Kralovánszky, Judit.

In: Anti-Cancer Drugs, Vol. 10, No. 6, 1999, p. 561-567.

Research output: Contribution to journalArticle

Katona, C, Tímár, F, Jeney, A, Fischel, JL, Milano, G, Pandi, E & Kralovánszky, J 1999, 'Modulation of 5-fluorouracil by 5-ethyl-2'deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities', Anti-Cancer Drugs, vol. 10, no. 6, pp. 561-567.
Katona, Csilla ; Tímár, Ferenc ; Jeney, A. ; Fischel, Jean L. ; Milano, Gerard ; Pandi, Erzsébet ; Kralovánszky, Judit. / Modulation of 5-fluorouracil by 5-ethyl-2'deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities. In: Anti-Cancer Drugs. 1999 ; Vol. 10, No. 6. pp. 561-567.
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abstract = "The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50 = 194 μM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55{\%}, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.",
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AU - Kralovánszky, Judit

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