5-Fluorouracil metabolism and cytotoxicity after pre-treatment with methotrexate or thymidine in human hypopharynx and colon carcinoma xenografts: a 19F-nuclear magnetic resonance spectroscopy study in vivo.
The metabolism of 5-fluorouracil (5-FU) was monitored non-invasively in two xenografts, a hypopharynx carcinoma and a colon carcinoma (CSM) by 19F-magnetic resonance spectroscopy following an i.v. bolus injection of 130 mg kg-1 5-FU. Both the level of fluoronucleotides (FNuc) and the tumor growth delay were significantly higher in the CSM colon carcinoma than in the hypopharynx carcinoma (both parameters, P < 0.001). Administration of 100 mg kg-1 methotrexate (MTX) at 15 h before treatment with 5-FU caused a significantly increased conversion of 5-FU to FNuc in both tumors (P < 0.05) as compared with the application of 5-FU alone. However, only in the CSM tumor was a significantly increased growth delay (P < 0.01) observed. Pre-treatment of both xenografts with 400 mg kg-1 thymidine enhanced the conversion of 5-FU to FNuc in both tumors. In the CSM tumour this treatment modality caused a significantly (P < 0.05) higher growth delay as compared with the results obtained with 5-FU alone, whereas in the hypopharynx carcinoma the additional application of thymidine caused no significant change in tumor growth. It is known that both thymidine and MTX can reduce the DNA-directed cytotoxicity of 5-FU, whereas the RNA-directed cytotoxicity is increased. It is concluded that the DNA-mediated toxicity may be more important in the hypopharynx carcinoma than in the CSM colon carcinoma. As a consequence, pre-treatment with MTX or thymidine enhances FNuc formation, although only in the CSM carcinoma is there an increased tumor growth delay. Thus, in the hypopharynx carcinoma the measurement of FNuc did not serve as a predictor for the treatment efficacy of the combined treatment modality. Pre-treatment with MTX did not influence the catabolism of 5-FU, whereas thymidine actually prolonged the half-life of 5-FU without alpha-fluoro-beta-alanine becoming detectable.
Department of Otolaryngology, Martin-Luther Universität, Halle, Germany.
R
R
Tausch-Treml
F
F
Baumgart
D
D
Ziessow
P
P
Köpf-Maier
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D010610:Pharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013936:Thymidine / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000964:Antimetabolites, Antineoplastic; D005462:Fluorine Radioisotopes; D005472:Fluorouracil; D013936:Thymidine; D008727:Methotrexate