Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo

Abstract

Summary 5-fluorouracil (5F-) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasivelv

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.…”

Biochemical modulation of the catabolism and tissue uptake of the anticancer drug 5‐fluorouracil by 5‐bromovinyluracil: Assessment with metabolic 19 F MR imaging

“…The rate-limiting step in this pathway is catalyzed by the enzyme dihydropyrimidine dehydrogenase, which can be found in large amounts in normal liver cells (5). Many questions regarding the pharmacokinetics and metabolism of 5-FU have been cleared up by 19 F magnetic resonance (MR) examinations of body fluids, tissue extracts, tumor-bearing animals, and cancer patients (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Most recently, the biomodulating effects of methotrexate, thymidine, ␣-interferon, N-(phosphonacetyl)-Laspartate, folinic acid, 5-benzylacyclouridine, and 5-ethynyluracil on the metabolism of 5-FU were determined by high-resolution 19 F MR spectroscopy (19)(20)(21)(22)(23)(24)(25)(26).…”

“…To this end, we used a chemical shift-selective (CHESS) 19 F MR imaging technique to selectively map the distribution of 5-FU and FBAL (34,35).…”

Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours

“…Using 19 F MRS, 5-FU and metabolites could be detected directly in the tumour and in the liver, in both preclinical animal investigations as well as in patient studies of systemically delivered 5-FU (Stevens et al, 1984;Wolf et al, 1990;reviewed in Martino et al, 2000). Studies in animals and patients suggest that the trapping of 5-FU and the amount of anabolites in the tumour correlate with response and may yield prognostic information on treatment outcome (McSheehy et al, , 1992Wolf et al, 1990Wolf et al, , 1998Findlay et al, 1993;Presant et al, 1994;Schlemmer et al, 1999). Furthermore, in MRS the area of the spectral peak is proportional to the concentration of the corresponding metabolite (absolute concentrations require calibration).…”