Biomedical subjects

M O Leach

Publications and source records attributed to M O Leach.

At least 109 records · Page 6Linked to original sources

PubMed1999

Nonrigid registration using free-form deformations: application to breast MR images.

In this paper we present a new approach for the nonrigid registration of contrast-enhanced breast MRI. A hierarchical transformation model of the motion of the breast has been developed. The global motion of the breast is modeled by an affine transformation while the local breast motion is described by a free-form deformation (FFD) based on B-splines. Normalized mutual information is used as a voxel-based similarity measure which is insensitive to intensity changes as a result of the contrast enhancement. Registration is achieved by minimizing a cost function, which represents a combination of the cost associated with the smoothness of the transformation and the cost associated with the image similarity. The algorithm has been applied to the fully automated registration of three-dimensional (3-D) breast MRI in volunteers and patients. In particular, we have compared the results of the proposed nonrigid registration algorithm to those obtained using rigid and affine registration techniques. The results clearly indicate that the nonrigid registration algorithm is much better able to recover the motion and deformation of the breast than rigid or affine registration algorithms.

Breast↗

PubMed1999

Comparison of MRI with CT for the radiotherapy planning of prostate cancer: a feasibility study.

This feasibility study was performed to evaluate the suitability of MRI in defining appropriate pelvic radiotherapy treatment volumes, and to compare MRI sequences with CT for prostate cancer radiotherapy. Five patients with localized prostate cancer, imaged with four MRI sequences (spin echo (SE) T1, turbo SE (TSE) T2, high resolution TSE (HR) T2, and FLASH 3D (F3D)), compared with their corresponding CT planning scans. Segmentation ability of the following pelvic structures: prostatic apex (PA), prostate, rectum, bladder and seminal vesicles (SV), were evaluated by three independent observers. They used a five point grading scale based on the anatomical definition of the organ boundary, tissue contrast and multiplanar display. Results were averaged for the group and for each sequence. There was no significant interobserver variation in the assessed scores (p > 0.1). The average scores (+/- 1 SD) for all pelvic structures assessed by each imaging sequence were CT 1.3 +/- 0.6; SE T1 2.4 +/- 0.9; TSE T2 2.4 +/- 0.7; HR T2 2.2 +/- 0.7 and F3D 3.4 +/- 0.6. Compared with CT, the average MR score for each assessed pelvic structure was higher with a trend for all transaxial MR sequences to provide improved segmentation of the PA and rectum. The F3D sequence scored highest as it provided multiplanar views and avoided the problem of partial volume averaging. MRI, compared with CT, appears to provide improved definition of pelvic treatment volumes but further work is required to confirm this and to address the issues of MRI associated distortion and dosimetry before MRI can be used routinely for pelvic radiotherapy planning.

Aged↗

PubMed1998

Carbogen breathing increases 5-fluorouracil uptake and cytotoxicity in hypoxic murine RIF-1 tumors: a magnetic resonance study in vivo.

The purpose of this study was to examine the effect of carbogen gas (95% O2-5% CO2) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo. In addition, we have explored the mechanisms by which carbogen can transiently affect the physiology of RIF-1 tumors. After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using 19F-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, carbogen caused a significant increase in the half-life (t(1/2)) of the elimination of 5FU by the tumor and a significant increase in growth inhibition. In 2-3-g tumors (group II), carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8-1.5-g tumors (group I), only the t(1/2) was slightly increased. These results suggested that tumor size was an important factor in the effect of carbogen on tumor physiology. Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors. However, 1H-MR images of RIF-1 tumors showed that carbogen caused a transient decrease in signal intensity, which correlated positively (P = 0.02) with tumor size, suggesting that larger tumors responded to carbogen by transiently increasing O2 uptake from the blood. 19F-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation (P = 0.001) with tumor size, implying greater hypoxia in larger tumors. We propose that carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space. 5FU transport is known to be pH dependent. Intra- and extracellular tumor pH was measured using 31P- and 19F-MRS, which showed that carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake. The pH gradient was unaffected in group I tumors. We conclude that carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood flow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that carbogen would be a valuable aid in clinical chemotherapy.

Animals↗

PubMed1998

Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized 31P measurements of response to treatment.

A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2-4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri-phosphate (TNTP) (p = 0.02) over 3 (+/-1) weeks were significantly associated with response, as were the levels of PME (p<0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (+/-1). PME at week 3 (+/-1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was -6%) compared with those measured on the same day (difference in TP was -29%).

Adult↗

PubMed1998

In vivo multiple spin echoes.

The demagnetizing field produced by the nuclear polarization can induce refocusing of multiple spin echoes. We show that multiple spin echoes can be observed in vivo with a clinical MR system at 1.5 T. Strategies for the spatial localization of the multiple spin echo signals are considered. Multiple spin echo studies in brain white matter and skeletal muscle in healthy volunteers are reported. The dependence of the signal amplitudes on the experimental parameters is compared with the theory. The sources of contrast for MRI and the perspectives for medical applications are discussed.

Brain↗

PubMed1998

A simple phantom to locate the origin of MRI ghost artefacts.

A simple pyramidal tube phantom has been designed to allow accurate location of a selected slice along the desired axis of a magnetic resonance scanner and to provide a check of the quality of slice selection. It is particularly helpful in locating the origin of any out-of-slice ghost artefacts. The geometry of the phantom allows the slice positions to be calculated readily.

Artifacts↗

PubMed1998

Absolute metabolite quantification by in vivo NMR spectroscopy: I. Introduction, objectives and activities of a concerted action in biomedical research.

By utilizing achievements and results of two previous concerted research projects on magnetic resonance imaging and spectroscopy (MRS), the EU BIOMED 1 Concerted Action on "Cancer and brain disease characterization and therapy assessment by quantitative MRS" was specifically aimed at: 1) developing at a multicentre level harmonized methodologies and protocols for quantitative and reproducible MRS measurements, as a basis for validating these procedures in well controlled clinical and experimental conditions; and 2) providing multicentre critical reviews on the present understanding of the significance of MRS parameters as possible new markers of diagnosis, prognosis and response to therapy. The programme comprised the following main areas of collaborative research and multicentre evaluation: a) development of methods and protocols for quality assessment, calibration and absolute metabolite quantification in in vivo localized, volume-selective MRS; b) design and validation of a new method for assessing localization performance in spectroscopic imaging (MRSI); c) interlaboratory comparison of different methods of signal processing and data analysis, for improving signal quantification in vivo and in vitro MRS spectra; d) quality assessment of high resolution MRS analyses of biological fluids; e) protocol for assembling a pilot data base of MR spectra of tumour extracts for pattern recognition analysis; f) multicentre review on evaluation of the significance of MRS parameters in monitoring lipid metabolism and function in cancer; and g) multicentre review on evaluation of drug pharmacokinetics and metabolism using MRS. The main results and conclusions of four multi-centre trials on items (a), (b) and (c), which involved 24 teams, are reported in the accompanying papers of this series.

Brain↗

PubMed1998

Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain.

We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

Adult↗

PubMed1998

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

To investigate the possible dependence of 5-fluorouracil (5FU) uptake in tumours on the intra- (pHi) and extracellular (pHe) pH, a pH gradient (deltapH) was imposed across the plasma membrane of ascites tumour cells in vitro, similar to that known to occur in some solid tumours in vivo, by incubation in media of PHe 5-8. A > or = 2:1 (intracellular/extracellular) accumulation of radiolabelled 5FU occurred after 5 min incubation of the cells with 0.5 mM 5FU at pHe of 5.0, 5.5 or 6.0. 5FU metabolism is slow under these conditions, and 5FU uptake was not affected by longer incubations up to 20 min, nor by the absence of a sodium gradient. pHi was estimated from the distribution of the weak acid, 5.5-dimethyl-2,4-oxazolidione ([14C]DMO) across the cell membrane. There was significant correlation between the intracellular/extracellular 5FU ratio and pHe (from pHe 6-8), deltapH and pHi (P < 0.02). Similar results were obtained with HT29 cells. Incubation with a drug that made plasma membranes permeable to H+ significantly decreased 5FU uptake in Lettre cells. The co-transport of 5FU may occur on a proton symport using the proton motive force of the deltapH.

Adenocarcinoma↗

PubMed1998

Improving calibration accuracy in gel dosimetry.

A new method of calibrating gel dosimeters (applicable to both Fricke and polyacrylamide gels) is presented which has intrinsically higher accuracy than current methods, and requires less gel. Two test-tubes of gel (inner diameter 2.5 cm, length 20 cm) are irradiated separately with a 10 x 10 cm2 field end-on in a water bath, such that the characteristic depth-dose curve is recorded in the gel. The calibration is then determined by fitting the depth-dose measured in water, against the measured change in relaxivity with depth in the gel. Increased accuracy is achieved in this simple depth-dose geometry by averaging the relaxivity at each depth. A large number of calibration data points, each with relatively high accuracy, are obtained. Calibration data over the full range of dose (1.6-10 Gy) is obtained by irradiating one test-tube to 10 Gy at dose maximum (Dmax), and the other to 4.5 Gy at Dmax. The new calibration method is compared with a 'standard method' where five identical test-tubes of gel were irradiated to different known doses between 2 and 10 Gy. The percentage uncertainties in the slope and intercept of the calibration fit are found to be lower with the new method by a factor of about 4 and 10 respectively, when compared with the standard method and with published values. The gel was found to respond linearly within the error bars up to doses of 7 Gy, with a slope of 0.233 +/- 0.001 s(-1) Gy(-1) and an intercept of 1.106 +/- 0.005 Gy. For higher doses, nonlinear behaviour was observed.

Acrylamides↗

PubMed1998

An investigation into the dosimetry of a nine-field tomotherapy irradiation using BANG-gel dosimetry.

BANG-gel dosimetry offers the potential for measuring the dose delivered by a radiotherapy treatment technique, in three dimensions, with high spatial resolution and good accuracy. The ability to measure comprehensively a 3D dose distribution is a major advantage of the gel dosimeter over conventional planar and point-based dosimeter devices, particularly when applied to the verification of complex dose distributions characteristic of intensity-modulated radiotherapy (IMRT). In this paper an in-house manufactured BANG-gel dosimeter was applied to study the dose distributions of two irradiation experiments for which the distributions were known: (i) a dosimetrically simple parallel-opposed irradiation, and (ii) a more complex nine-field 'static tomotherapy' intensity-modulated irradiation delivered with the Nomos MIMiC. The uniform distribution in (i) allowed a study of the magnetic resonance (MR) imaging parameters to achieve an optimal trade-off between noise and image resolution (optimum image resolution for the Siemens 1.5T Vision system was determined to be approximately 0.8 mm2 with a slice thickness of 2 mm). The spatial uniformity of gel sensitivity to radiation was found to depend strongly on the presence of oxygen, which must be eliminated for the gel dosimeter to be of use. The gel dosimeter was found to agree well with predicted dose distributions and accurately measured the steep penumbral fall-off of dose, even after many days, proving its potential for the verification of IMRT distributions. In the nine-field IMRT delivery (ii) the predicted dose was computed by both an in-house 'component-delivery' dose algorithm and the Peacock planning-system dose algorithm. Good agreement was found between the two algorithms despite the latter's omission of the change in penumbral characteristics with aperture-size during delivery, lack of inhomogeneity correction and approximate modelling of leaf leakage. These effects were found to be small for the problem studied. The predicted distribution agreed well with the gel-measured distribution at medium and high doses (50-90% isodose lines) although differences of up to 10% were observed at lower doses (30% isodose line). The gel dosimeter was found to have the potential to verify IMRT distributions but required considerable care to achieve accurate results. Attention was required to achieve uniformity of gel sensitivity (to prevent oxygen contamination), and in the calibration process.

Acrylamide↗

PubMed1997

Implementation and evaluation of frequency offset corrected inversion (FOCI) pulses on a clinical MR system.

FOCI pulses are a variant of hyperbolic secant pulses in which the RF amplitude, RF frequency, and gradient waveform are all modulated by the same function A(t). This increases the usable gradient amplitude without requiring a corresponding increase in RF amplitude. In this paper the implementation and inversion profiles of FOCI pulses on a clinical MR system are described, showing improved slice definition and chemical-shift offset behavior. Their adiabatic behavior is confirmed, and their use with an ISIS sequence for localized MRS is illustrated. Finally the effects of waveform digitization are considered, and the implications for SAR and dB/dt are discussed.

Contrast Media↗

PubMed1997

Magnetic resonance imaging (MRI): considerations and applications in radiotherapy treatment planning.

The emerging utilisation of conformal radiotherapy (RT) planning requires sophisticated imaging modalities. Magnetic resonance imaging (MRI) has introduced several added imaging benefits that may confer an advantage over the use of computed tomography (CT) in RT planning such as improved soft tissue definition, unrestricted multiplannar and volumetric imaging as well as physiological and biochemical information with magnetic resonance (MR) angiography and spectroscopy. However, MRI has not yet seriously challenged CT for RT planning in most sites. The reasons for this include: (1) the poor imaging of bone and the lack of electron density information from MRI required for dosimetry calculations; (2) the presence of intrinsic system-related and object-induced MR image distortions; (3) the paucity of widely available computer software to accurately and reliably integrate and manipulate MR images within existing RT planning systems. In this review, the basic principals of MRI with its present potential and limitations for RT planning as well as possible solutions will be examined. Methods of MRI data acquisition and processing including image segmentation and registration to allow its application in RT planning will be discussed. Despite the difficulties listed, MRI has complemented CT-based RT planning and in some regions of the body especially the brain, it has been used alone with some success. Recent work with doped gel compounds allow the MRI mapping of dose distributions thus potentially providing a quality assurance tool and in a manner analogous to CT, the production of dose-response information in the form of dose volume histograms. However, despite the promise of MRI, much development research remains before its full potential and cost-effectiveness can be assessed.

Abdominal Neoplasms↗

PubMed1997

A pharmacokinetic and pharmacodynamic study in vivo of human HT29 tumours using 19F and 31P magnetic resonance spectroscopy.

19F-MRS (magnetic resonance spectroscopy) was used to study the pharmacokinetics of 5-fluorouracil (5-FU) in human (HT29) tumour xenografts, with and without pretreatment of the mice using either thymidine (40 min) or interferon-alpha (2 and 24 h). A 200 mg/kg i.p. bolus dose of 5-FU was eliminated from control tumours with a t1/2 of 25.4 +/- 2 min (mean +/- SEM, n = 11), while both thymidine (500 mg/kg) and interferon (50,000 IU/mouse) significantly increased t1/2 to 36.5 +/- 6.1 (n = 5) and 48.1 +/- 13.6 min (n = 4), respectively (P = 0.04, Gabriel's ANOVA). Thymidine increased 5-FU anabolism to cytotoxic 5-fluoronucleotides, and decreased the amount of tumour catabolites; the latter probably recirculated from liver since isolated HT29 cells did not catabolize 5-FU. These in vivo observations were confirmed by 19F-MRS quantification of tumour extracts. Interferon did not significantly affect 5-FU metabolism in the tumour or liver, nor the 5-FU t1/2 in liver. Treatment of tumours with 5-FU or interferon had no effect on tumour growth, whereas the combination strongly inhibited growth. 31P-MRS of HT29 tumours showed that 2 and 24 h after i.p. injections of interferon there was a significant increase in the pHint of 0.3 +/- 0.04 units (P = 0.002), while pHext and the tumour NTP/Pi ratio were unchanged. The large increase in the negative pH gradient (-delta pH) across the tumour plasma membrane caused by interferon suggest the delta pH may be a factor in tumour retention of 5-FU, as recently shown in isolated tumour cells.

Animals↗

PubMed1997

Quantification of phosphorus metabolites in human calf muscle and soft-tissue tumours from localized MR spectra acquired using surface coils.

Metabolite concentrations determined from MR spectra provide more specific information than peak area ratios. This paper presents a method of quantification that allows metabolite concentrations to be determined from in vivo 31P MR spectra acquired using a surface coil and ISIS localization. Corrections for the effects of B1 field inhomogeneity produced by surface coils are based on a measured and calibrated spatial sensitivity field map for the coil. Account is taken of imperfections in pulse performance, coil loading effects and relaxation effects, the latter making use of published metabolite relaxation times. The technique is demonstrated on model solutions. The concentrations of the main 31P metabolites in normal human calf muscle measured using this method are [PCr] = 26.9 +/- 4.1 mM; [Pi] = 3.6 +/- 1.2 mM; [NTP] = 6.8 +/- 1.8 mM. Quantification of spectra acquired from soft-tissue tumours in patients both pre- and post-treatment showed that changes in metabolite concentrations are more sensitive to metabolic changes than changes in peak area ratios.

Adenosine Triphosphate↗

PubMed1997

MRI study of hepatic tumours following high intensity focused ultrasound surgery.

High intensity, focused ultrasound has considerable potential as a non-invasive surgical technique, with applications which include the treatment of benign prostatic hyperplasia and the elimination of metastatic disease in the liver. In this study, the use of MRI for treatment planning and subsequent monitoring of ultrasound therapy in the liver has been evaluated. In an experimental model both tumour bearing and normal liver lobes were treated invasively with high intensity focused beam ultrasound surgery. Subsequent changes in the tissue properties were investigated using MRI, in combination with the intravenous contrast agent, Gd-DTPA. The repair of ultrasound damaged tissue was followed until 8 weeks after treatment. The appearance of the MR images was compared with histological sections prepared from parallel experiments. Imaging and histology results showed excellent agreement, illustrating that MRI is well suited to the non-invasive observation of the effects of high intensity focused ultrasound therapy on tissue. Thus, as the clinical potential of ultrasound surgery is realized, MRI, together with the use of contrast agents, will be invaluable both in treatment planning and in monitoring the progress of a treated tumour.

Animals↗

PubMed1996

Simultaneous localized 1H STEAM/31P ISIS spectroscopy in vivo.

A sequence for simultaneous acquisition of 1H STEAM and 31P ISIS spectra is described, and 1H and 31P spectra obtained simultaneously from the same volume of interest in both a phantom and a volunteer are presented. The STEAM and ISIS parts of the sequence use a common gradient scheme that is also used during the localized shimming process, partially compensating for eddy current effects. It is demonstrated that this method of simultaneous multinuclear spectroscopy does not compromise the localization performance of the sequence.

Brain↗

PubMed1996

Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha.

PURPOSE: To measure plasma 5-fluorouracil (5-FU) levels using high-performance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-FU evaluated using 19F magnetic resonance spectroscopy (MRS), during a protracted venous infusion (PVI) with or without interferon-alpha. METHODS: Patients receiving PVI 5-FU (300 mg/m2/day) with or without interferon-alpha (5 x 10(6) units 3 times per week), had 2 weekly plasma 5-FU levels evaluated using reverse-phase ion-pairing HPLC. These samples were drawn just prior to the patient undergoing MRS using a 1.5T Siemens Magnetom whole body magnetic resonance system with a 16 cm surface coil placed over normal liver or metastatic tumour. Semi-quantitated MRS values were compared with the plasma 5-FU levels using linear regression analysis. Data were available from patients given interferon-alpha with PVI 5-FU from day 1 or at the point of 5-FU refractory disease. RESULTS: A total of 30 patients were studied. Plasma 5-FU concentrations while on a protracted venous infusion varied from <25 ng/ml (0.192 mu M) to 25,000 ng/ml (192 mu M). A high plasma 5-FU concentration was associated with an increase in patient toxicity. Patients given interferon-alpha with 5-FU had higher median plasma 5-FU levels higher than patients on 5-FU alone (6138 vs. 218 ng/ml; p = 0.03). There was no correlation between the plasma 5-FU concentration and tumour response. A comparison of the plasma 5-FU data to the MRS studies in normal liver revealed a positive correlation between plasma 5-FU and liver catabolite signal (r = 0.68; p = 0.016) but a negative correlation with the log plasma 5-FU concentration and 5-FU liver signal (r = -0.63; p = 0.022). The patients experiencing toxicity, in addition to having a higher plasma 5-FU concentration did not exhibit a liver 5-FU signal, while the reverse was true for those having no toxicity. CONCLUSIONS: Plasma 5-FU levels may show greater interpatient variation when given as a protracted venous infusion. Levels of 5-FU correlated with treatment toxicity but not with anti-tumour activity. The addition of interferon-alpha to 5-FU increases plasma 5-FU levels. MRS findings suggest patients with low plasma 5-FU levels have higher 5-FU levels in normal liver tissue than in those with higher plasma levels.

Antimetabolites, Antineoplastic↗