5-FLUOROURACIL METABOLISM AND CYTOTOXICITY AFTER PRETREATMENT WITH METHOTREXATE OR THYMIDINE IN HUMAN HYPOPHARYNX AND COLON-CARCINOMA XENOGRAFTS - A F-19-NUCLEAR MAGNETIC-RESONANCE SPECTROSCOPY STUDY IN-VIVO

The metabolism of 5-fluorouracil (5-FU) was monitored non-invasively i n two xenografts, a hypopharynx carcinoma and a colon carcinoma (CSM) by F-19-magnetic resonance spectroscopy following an i.v. bolus inject ion of 130 mg kg(-1) 5-FU. Both the level of fluoronucleotides (FNuc) and the tumour growth delay were significantly higher in the CSM colon carcinoma than in the hypopharynx carcinoma (both parameters, P <0.00 1). Administration of 100 mg kg(-1) methotrexate (MTX) at 15 h before treatment with 5-FU caused a significantly increased conversion of 5-F U to FNuc in both tumours (P <0.05) as compared with the application o f 5-FU alone. However, only in the CSM tumour was a significantly incr eased growth delay (P <0.01) observed. Pre-treatment of both xenograft s with 400 mg kg(-1) thymidine enhanced the conversion of 5-FU to FNuc in both tumours. In the CSM tumour this treatment modality caused a s ignificantly (P <0.05) higher growth delay as compared with the result s obtained with 5-FU alone, whereas in the hypopharynx carcinoma the a dditional application of thymidine caused no significant change in tum our 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 mo re important in the hypopharynx carcinoma than in the CSM colon carcin oma. As a consequence, pre-treatment with MTX or thymidine enhances FN uc formation, although only in the CSM carcinoma is there an increased tumour growth delay. Thus, in the hypopharynx carcinoma the measureme nt of FNuc did not serve as a predictor for the treatment efficacy of the combined treatment modality. Pre-treatment with MTX did not influe nce the catabolism of 5-FU, whereas thymidine actually prolonged the h alf-life of 5-FU without alpha-fluoro-beta-alanine becoming detectable .