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

The aim of the present studies was to elucidate the effects and optimal mod ulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour ef ficacy. pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-2 6 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measu re the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluraci l and uridine in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine m onophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h be fore 5-FU, selectively enhanced the antitumour action of 5-FU, without sign ificantly increasing its toxic side-effects, thus resulting in an approxima tely 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 mu M, and that of 5- ethyluracil, as the major metabelite of EtdUrd, was 421 mu M. It is of inte rest that EtdUrd pretreatment did not change the maximal plasma concentrati on of 5-FU; however, the half-life of the terminal elimination increased fr om 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose sig nificantly (P < 0.05). After the combined treatment, the maximal concentrat ion of dihydro-5-fluorouracil in the plasma decreased from 61.06 mu M to 29 .70 mu M (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 treat ment. EtdUrd also caused a moderate increase in the intratumoral level of F dUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concen tration in the plasma from 18 mu M to a maximum of 249 mu M, 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, prolong ing the plasma and intratumoral concentrations of 5-FU and, at the same tim e, offering protection to normal organs by increasing the endogenous uridin e level.