Prolonged retention of high concentrations of 5-fluorouracil in human and murine tumors as compared with plasma

Abstract

Concentrations of 5-fluorouracil (5-FU) and its active metabolite 5-fluoro-2'-deoxy-5'-monophosphate (FdUMP) were measured in biopsy specimens of tumor tissue, normal mucosa, metastatic liver nodules, and normal liver tissue obtained from 39 patients and in two murine colon tumors (colon 26 and colon 38) after a single injection of 5FU at a therapeutic dose (500 mg/m2 and 100 mg/kg, respectively). These data were compared with plasma concentrations. Peak plasma concentrations (300-500 microM) of 5FU were comparable in human and murine plasma. The half-life of plasma elimination (during the period from 15 to 120 min) in both mouse and man ranged from 10 to 20 min, whereas at between 2 and 8 h, plasma concentrations varied from 0.1 to 1 microM, the half-life being about 100 min. In both species, 5FU could be measured in plasma at concentrations ranging from 0.01 to 1 microM for several days after 5FU treatment. 5FU concentrations in tissue samples obtained from 14 patients were measured during the time range of 1-6 h, those in samples taken from 7 patients, during the interval of 19-27 h; and those in samples obtained from 18 patients, within the interval of 40-48 h after injection. 5FU tumor concentrations varied between 0.78-21.6, 0.44-6.1, and 0.17-10.8 mumol/kg wet wt., respectively. Some of the 48-h samples were obtained from patients who had received leucovorin plus 5FU; coadministration of leucovorin did not alter 5FU tissue concentrations. At between 4 and 48 h, the tissue concentration/plasma concentration ratio was at least 10. 5FU concentrations in murine tumors were measured for up to 10 days after 5FU administration, with plateau 5FU tumor concentrations being about 50 mumol/kg wet wt. in colon 38 and about 200 mumol/kg wet wt. in colon 26 at 2 h after treatment; after 4 days, values of 0.5 and 4.8 mumol/kg, respectively, were obtained and after 10 days, respective concentrations of 0.1 and 0.07 mumol/kg were detected. The FdUMP concentrations measured in colon 26 and colon 38 tumors were 214 and 46 pmol/g, respectively, at 2 h after 5FU administration, and these values subsequently decreased to about 15 pmol/g in both tumors. In human tumors the initial FdUMP concentration ranged from 10 to 1000 pmol/g; at later time points the level of FdUMP was just above the detection limit of the assay. In liver metastases, high 5FU concentrations seemed to be related to high levels of FdUMP, which was likely of importance for the antitumor effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells

“…At a lower pHe, in which the -ApH is large, such as occurs in solid tumours, there would be an enhancement of 5FU uptake, whereas normal cells (in which ApH is usually positive) will tend to exclude 5FU. In solid tumours this could lead to an accumulation of 5FU relative to other normal tissues, which is precisely what has been recorded in biopsies (Peters et al, 1993) and also by non-invasive '9F MRS in animal models and in the clinic (Findlay et al, 1993;Presant et al, 1994). The hypothesis suggests potential means of manipulating the tumour pH environment for therapeutic gain.…”

“…Enhanced retention has also been shown to be significantly associated with response Findlay et al, 1993), perhaps because higher concentrations of 5FU will sustain its anti-tumour effects by favouring the lasting presence of toxic metabolites at target tissue sites (Peters et al, 1993). The elimination half-lives (t112) of 5FU in the VX2 tumour of the rabbit , and the Walker 256 adenocarcinoma of the rat (El-Tahtawy and Wolf, 1991), were found to be about 1 h (63-73.2 and 42.2-59.4 min respectively), and greatly exceed the t 12 of 5FU in rat plasma (Au et al, 1983), which is similar to that reported in humans (5-15 min) (Cohen et al, 1982).…”

Transcriptional profiling of MCF7 breast cancer cells in response to 5‐Fluorouracil: Relationship with cell cycle changes and apoptosis, and identification of novel targets of p53

“…10 5-FU cytotoxicity (and in consequence, clinical response) is influenced by the tissue concentration of the folate form of 5-FU, which in turn depends on the type of administration, whether oral prodrug, intravenous continuous infusion or bolus administration. 11,12 In fact, it has been postulated that the better response to the oral 5-FU prodrug 5DFUR is a consequence of the higher concentrations of intracellular 5-FU in neoplastic cells achieved after its administration. 13 To elucidate the global mechanisms of 5-FU cytotoxicity in breast cancer cells, and the molecular pathways involved in its activity, we studied gene expression profiles by microarray analysis of the well-known MCF7 breast adenocarcinoma cell line after treatment with 2 concentrations of 5-FU.…”

DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents?

“…Therefore, we measured DTD levels in a number of human normal (from colon, lung, liver, blood and head and neck) and neoplastic tissues (from colon, lung and head and neck) to determine whether, and if so in which tumour types, E09 would exert selectivity. The activity of two one-electron reductases, Cb5R and CP450R, was measured for comparison and because of their possible role in the activation of E09 under hypoxia (Plumb et al, 1994b,c;Robertson et al, 1994 (Peters et al, 1993 All the lung specimens were obtained from patients with non-small-cell lung cancer (NSCLC) undergoing radical resection. Four tumours were classified as squamous cell carcinoma (SCC), one as an adenocarcinoma (AD), one as combined adenosquamous (AS) and one as large cell (LC).…”