A pharmacokinetic and pharmacodynamic study In vivo of human HT29 tumours using 19F and 31P magnetic resonance spectroscopy

• Published in: European journal of cancer (1990) 1997-12, Vol.33 (14), p.2418-2427
• Main Authors: McSheehy, P.M.J., Seymour, M.T., Ojugo, A.S.E., Rodrigues, L.M., Leach, M.O., Judson, I.R., Griffiths, J.R.
• Format: Article
• Language: English
• Subjects: 5-fluorouracil; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; Fluorouracil - pharmacokinetics; General aspects; HT29 Cells - drug effects; HT29 Cells - metabolism; human tumours; Humans; Interferon-alpha - pharmacology; interferon-α; Investigative techniques, diagnostic techniques (general aspects); Liver Neoplasms, Experimental - metabolism; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Nude; Miscellaneous. Technology; Neoplasm Transplantation; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; pharmacokinetics; phosphorus/fluorine magnetic resonance spectroscopy; Thymidine - pharmacology; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(97)00336-5

19F-MRS (magnetic resonance spectroscopy) was used to study the pharmacokinetics of 5-fluorouracil (5-FU) in human (HT29) tumour xenografts, with and without pretreatment of the mice using either thymidine (40 min) or interferon-α (2 and 24 h). 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 min (mean ± SEM, n = 11), while both thymidine (500 mg/kg) and interferon (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-fluoronucleotides, and decreased the amount of tumour catabolites; the latter probably recirculated from liver since isolated HT29 cells did not catabolise 5-FU. These in vivo observations were confirmed by 19F-MRS quantification of tumour extracts. Interferon did not significantly affect 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. 31P-MRS of HT29 tumours showed that 2 and 24 h after i.p. injections of interferon there was a significant increase in the pH int of 0.3 ± 0.04 units ( P = 0.002), while pH ext and the tumour NTP/Pi ratio were unchanged. The large increase in the negative pH gradient (−Δ pH) across the tumour plasma membrane caused by interferon suggests the Δ pH may be a factor in tumour retention of 5-FU, as recently shown in isolated tumour cells.