5-Ethyl-2'-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil

Judit Kralovánszky, Csilla Katona, András Jeney, Erzsébet Pandi, Paul Noordhuis, Valéria Erdélyi-Tóth, László Ötvös, Péter Kovács, Clasina L. Van der Wilt, Godefridus J. Peters

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Abstract

The aim of the present studies was to elucidate the effects and optimal modulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively enhanced the antitumour action of 5-FU, without significantly increasing its toxic side-effects, thus resulting in an approximately three times higher therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg EtdUrd administration - i.e. at the time of 5-FU treatment - the plasma concentration of EtdUrd was 269 μM, and that of 5-ethyluracil, as the major metabolite of EtdUrd, was 421 μM. It is of interest that EtdUrd pretreatment did not change the maximal plasma concentration of 5-FU; however, the half-life of the terminal elimination increased from 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose significantly (P < 0.05). After the combined treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma decreased from 61.06 μM to 29.70 μM (P < 0.01). The intratumoral concentrations of 5-FU were 34%-158% higher 6-96 h after the combined treatment than after the single 5-FU treatment. EtdUrd also caused a moderate increase in the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concentration in the plasma from 18 μM to a maximum of 249 μM, and the level remained high for longer than 6 h. The present studies indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at the same time, offering protection to normal organs by increasing the endogenous uridine level.

Original languageEnglish
Pages (from-to)675-684
Number of pages10
JournalJournal of cancer research and clinical oncology
Volume125
Issue number12
DOIs
Publication statusPublished - Dec 6 1999

Keywords

  • 5-Ethyl-2'-deoxyuridine
  • 5-Fluorouracil
  • Antitumour activity
  • Modulation
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kralovánszky, J., Katona, C., Jeney, A., Pandi, E., Noordhuis, P., Erdélyi-Tóth, V., Ötvös, L., Kovács, P., Van der Wilt, C. L., & Peters, G. J. (1999). 5-Ethyl-2'-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil. Journal of cancer research and clinical oncology, 125(12), 675-684. https://doi.org/10.1007/s004320050333