5-fluorouracil metabolism and cytotoxicity after pre-treatment with methotrexate or thymidine in human hypopharynx and colon carcinoma xenografts: a19F-nuclear magnetic resonance spectroscopy study in vivo

Abstract

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.

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma

“…Our 19 F MRS results show that the more sensitive C26-10 tumour exhibits a significantly higher conversion of 5-FU to fluoronucleotides (cytotoxic anabolites) compared to the insensitive, more rapidly growing C26-B tumour (C max and AUC in Table 1). These results support previous findings that positive therapy response correlates with the concentration of anabolites achieved in tumour tissue, either directly or with the aid of modulators (McSheehy et al, 1989(McSheehy et al, , 1992Koutcher et al, 1991;Sijens and Ng, 1992;Findlay et al, 1993;Tausch-Treml et al, 1996;Holland et al, 1997). The broad anabolite peak observed in Figure 1 represents the complete family of fluoronucleotides (mono-, di-, triphosphates; oxy-and deoxy forms) which cannot be further distinguished with in vivo 19 F MRS.…”

Monitoring fluoropyrimidine metabolism in solid tumors with in vivo 19F magnetic resonance spectroscopy

“…Although at the low FU dose no anabolites were detected in normal liver tissue, after injection of low-dose 5FU combined with thymidine anabolite resonances were observed in the liver. TauschTreml et al [94] observed enhanced conversion of FU to fluoronucleotides as well as an increased half-life of FU in both human hypopharynx carcinoma and colon carcinoma xenografts when co-treated with thymidine (400 mg/kg) was performed. The plateau level of fluoronucleotides 50-60 min after injection of a FU bolus (130 mg/kg) divided by the initial concentration was 0.18 ± 0.086 for the hypopharynx carcinoma with thymidine co-treatment, 0.13 ± 0.068 for the corresponding controls and 0.36 ± 0.125 for the colon carcinoma with thymidine co-treatment, 0.24 ± 0.11 for the corresponding controls.…”

“…FdUMP (DNA-directed toxicity) is present at much lower concentrations than FUTP (RNA-directed toxicity) and is expected to make a negligible contribution to the fluoronucleotide resonance. Thus, it was speculated by the authors [94] that in tumors for which DNA-directed toxicity is more important than RNA-directed toxicity, addition of thymidine to FU therapy may lead to an increase in fluoronucleotide levels without affecting tumor cytotoxicity. This seems to be the case for hypopharynx carcinoma and may explain why anabolite formation did not serve as a predictor for the efficacy of the combined treatment with this tumor.…”

“…For all regimens, very similar patterns of metabolism were found, possibly due to extensive polyglutamation of MTX in the Walker carcinosarcoma cells, which prevents MTX efflux and sustains intracellular MTX levels irrespective of the administration schedule. In the study by Tausch-Treml et al [94], human hypopharynx carcinoma and colon carcinoma xenografts were treated with a 100 mg/kg bolus of MTX 15 h before treatment with a 130 mg/kg bolus of FU. In both tumor lines enhanced conversion of FU to fluoronucleotides as well as an increased half-life of FU was observed when co-treated with MTX.…”

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high‐field 19F‐NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

“…routes) or modulators to enhance F-Nuctd production generally results in improved therapy response. 61,62,64,[67][68][69][70][72][73][74] The conversion of FU into FUTP and FdUMP via enzyme-catalyzed multistep reactions 31 is an essential prerequisite for cytotoxicity via RNA-or DNA-directed mechanisms. Thus, the amounts of F-Nuctd produced intracellularly can be considered to be a measure of the cytotoxic potential of a given fluoropyrimidine therapy protocol, as shown in animal models 61,68,105 and for ovarian cancer.…”