A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY IN-VIVO OF HUMAN HT29 TUMORS USING F-19 AND P-31 MAGNETIC-RESONANCE SPECTROSCOPY

F-19-MRS (magnetic resonance spectroscopy) was used to study the pharm acokinetics of 5-fluorouracil (5-FU) in human (HT29) tumour xenografts , with and without pretreatment of the mice using either thymidine (40 min) or interferon-alpha (2 and 24h). A 200 mg/kg i.p. bolus dose of 5-FU was eliminated from control tumours with a t(1/2) of 25.4 +/- 2 m in (mean +/- SEM, n = 11), while both thymidine (500 mg/kg) and interf eron (50 000 IU/mouse) significantly increased t(1/2) to 36.5 +/- 6.1 (n = 5) and 48.1 +/- 13.6 min (n = 4), respectively (P = 0.04, Gabriel 's ANOVA). Thymidine increased 5-FU anabolism to cytotoxic 5-fluoronuc leotides, and decreased the amount of tumour catabolites; the latter p robably recirculated from liver since isolated HT29 cells did not cata bolise 5-FU. These in vivo observations were confirmed by F-19-MRS qua ntification of tumour extracts. Interferon did not significantly affec t 5-FU metabolism in the tumour or liver, nor the 5-FU t(1/2) in liver . Treatment of tumours with 5-FU or interferon had no effect on tumour growth, whereas the combination strongly inhibited growth. P-31-MRS o f HT29 tumours showed that 2 and 24 h after i.p. injections of interfe ron there was a significant increase in the pH(int), of 0.3 +/- 0.04 u nits (P = 0.002), while pH(ext) and the tumour NTP/Pi ratio were uncha nged. The large increase in the negative pH gradient (-Delta pH) acros s the tumour plasma membrane caused by interferon suggests the a pH ma y be a factor in tumour retention of 5-FU, as recently shown in isolat ed tumour cells. (C) 1997 Elsevier Science Ltd.