The Experts below are selected from a list of 141 Experts worldwide ranked by ideXlab platform

Arend Heerschap - One of the best experts on this subject based on the ideXlab platform.

  • 5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy
    Magnetic resonance in medicine, 2005
    Co-Authors: Y.j.l. Kamm, Arend Heerschap, G.j.e. Rosenbusch, Ivonne M.c.m. Rietjens, Jacques Vervoort, D.j.t. Wagener
    Abstract:

    High-resolution 19F NMR spectroscopy at 9.4 T was used to study the difference in the metabolite pattern of 5-fluorouracil (5-FU) between viable and necrotic tissues of C38 murine colon tumors grown in C57BI/6 mice. Studies were performed on perchloric acid extracts of these tumor fractions after 5-FU treatment. The 19F nuclear magnetic resonance spectra exhibited resonances representing 5-FU, the catabolites alpha-fluoro-beta-ureidopropionic acid and Alpha-Fluoro-Beta-Alanine, as well as several fluoronucleotide anabolites. The absolute concentrations of anabolites and catabolites and the anabolite-to-catabolite ratio were significantly lower in the necrotic fraction than in the viable tumor fraction 50 min after administration of 5-FU, whereas the absolute concentration of 5-FU was the same. Therefore, in 5-FU metabolism studies with NMR spectroscopy, it is important to consider the necrotic contribution to the tumor volume.

  • In vivo monitoring of capecitabine metabolism in human liver by 19fluorine magnetic resonance spectroscopy at 1.5 and 3 Tesla field strength.
    Cancer research, 2003
    Co-Authors: Hanneke W. M. Van Laarhoven, Y.j.l. Kamm, Dennis W. J. Klomp, Cornelis J. A. Punt, Arend Heerschap
    Abstract:

    In metastatic colorectal cancer the oral 5-fluorouracil (5FU) prodrug capecitabine is used with increasing frequency as an alternative to i.v. 5FU administration. The rate of conversion of capecitabine into 5'deoxy-5-fluorouridine has been related to tumor response, and 5FU catabolites have been associated with 5FU-related systemic toxicity. Here we demonstrate for the first time that capecitabine, its metabolites 5'deoxy-5-fluorocytidine and 5'deoxy-5-fluorouridine, and its catabolites 5-fluoro-ureido-propionic acid, Alpha-Fluoro-Beta-Alanine, and Alpha-Fluoro-Beta-Alanine-bile acid conjugate can be monitored in vivo by (19)fluorine magnetic resonance spectroscopy ((19)F MRS) in the liver of patients with metastatic colorectal cancer. Moreover, we demonstrate an improved signal-to-noise ratio and spectral resolution of the (19)F MRS spectra when measurements are performed at 3 T field strength as compared with measurements at the common clinical field strength of 1.5 T. We conclude that assessment of capecitabine metabolism in patients by (19)F MRS is a promising noninvasive tool for the prediction of its efficacy and toxicity, especially at the now currently available clinical field strength of 3 T.

  • Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver.
    Magnetic resonance in medicine, 2003
    Co-Authors: Dennis W. J. Klomp, Hanneke W. M. Van Laarhoven, Arno P. M. Kentgens, Arend Heerschap
    Abstract:

    Fluorine MR spectroscopy ((19)F MRS) is an indispensable tool for assessing the pharmacokinetics of fluorinated drugs. Since the metabolism of 5-fluorouracil (5FU), a frequently used cytotoxic drug, is expected to be different in normal liver and in tumor tissue, spatial localization is required for detection by MRS. In this study, three independent signal-to-noise ratio (SNR) optimizations were combined to enable chemical shift imaging (CSI) as a localization method in the detection of 5FU and its metabolites in tumor tissue. First, the hardware was optimized by using circularly polarized coils together with integrated preamplifiers. Second, the optimal pulse angle (Ernst angle) was determined on the basis of T(1) relaxation time measurements of 5FU. Finally, averaging of CSI phase-encoding steps was optimized by using the applied Hamming filter as a weighting function. The combination of these three methods enables the in vivo detection of 5FU and Alpha-Fluoro-Beta-Alanine (FBAL) by (19)F MRS, localized in three dimensions in tumor and liver tissue at a time resolution of 4 min at 1.5 Tesla.

U. Haberkorn - One of the best experts on this subject based on the ideXlab platform.

  • Biochemical modulation of the catabolism and tissue uptake of the anticancer drug 5-fluorouracil by 5-bromovinyluracil: Assessment with metabolic 19F MR imaging
    Magnetic resonance in medicine, 1999
    Co-Authors: Gunnar Brix, M.e. Bellemann, U. Haberkorn
    Abstract:

    Using chemical shift-selective (19)F magnetic resonance (MR) imaging, we investigated the biomodulating action of 5-bromovinyluracil (BVU) on the degradation of the anticancer drug 5-fluorouracil (5-FU) to its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) and the tissue uptake of 5-FU in ACI rats with transplanted Morris hepatoma. Rats in the control group (n = 7) received 200 mg/kg body weight of 5-FU intravenously, whereas the rats in the BVU group (n = 7) additionally received 30 mg/kg body weight of BVU intraperitoneally about 45 min before 5-FU injection. In each animal examination, three selective (19)F MR images were acquired sequentially after 5-FU administration with an acquisition time of 32 min each: an early 5-FU image (dominant Fourier line, 8 min p.i.) that characterized the early uptake of the drug into the various tissues, an FBAL image (dominant Fourier line, 56 min p.i.) that reflected the catabolism of the drug, and a late 5-FU image (dominant Fourier line, 78 min p.i.) that assessed the retention ("trapping") of unmetabolized 5-FU and its MR-visible anabolites. Pretreatment with BVU resulted in a highly statistical significant decrease (P 0.7). Moreover, our results indicate that 5-FU tumor uptake is not only dependent on the plasma concentration of unmetabolized 5-FU but is also determined by tumor-specific factors, these showing considerable variations between individual neoplasms. Magn Reson Med 42:936-943, 1999.

  • Direct detection of intratumoral 5-fluorouracil trapping using metabolic 19F MR imaging.
    Magnetic resonance imaging, 1999
    Co-Authors: Gunnar Brix, M.e. Bellemann, Ludwig Gerlach, U. Haberkorn
    Abstract:

    The effective use of 5-fluorouracil (5-FU) in cancer therapy requires the noninvasive assessment of its transport, metabolism, and retention ("trapping") in the different tissues of the organism, particularly in the tumor. We used a chemical-shift selective 19F magnetic resonance (MR) imaging technique to map selectively 5-FU and its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) in six ACI rats bearing Morris hepatoma. After i.v. administration of 200 mg/kg-bw 5-FU, three metabolic MR maps were acquired consecutively in each animal: 1) an early 5-FU image (5-37 min post-injection (p.i.); dominant Fourier line, 8 min p.i.) characterizing the early uptake of 5-FU into the various tissues; 2) an FBAL image (40-72 min p.i.; dominant Fourier line, 56 min p.i.) reflecting the catabolism of the drug; and 3) a late 5-FU image (75-107 min p.i.; dominant Fourier line, 78 min p.i.) to assess the retention of unmetabolized 5-FU and its MR-visible anabolites. In the early 5-FU maps, the drug was detected in all major organs (e.g., heart, liver, kidneys) as well as in the muscular system. The FBAL maps showed no FBAL accumulation in the hepatoma which reveals that the tumor cells have lost hepatocellular functions relevant for 5-FU catabolism. On the late 5-FU maps, a significant amount of 5-FU was detected in only one of the six Morris hepatomas. The observation in this rat verifies directly that 5-FU can be trapped in solid tumors. The images, moreover, emphasize the necessity of acquiring spatially-resolved MR data to detect metabolic tumor heterogeneity.

  • Intra- and extracellular fluorouracil uptake: assessment with contrast-enhanced metabolic F-19 MR imaging.
    Radiology, 1998
    Co-Authors: Gunnar Brix, M.e. Bellemann, Ludwig Gerlach, U. Haberkorn
    Abstract:

    PURPOSE: To assess the extra- and intracellular uptake of the anticancer drug fluorouracil and its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) at gadolinium-enhanced fluorine-19 magnetic resonance (MR) imaging. MATERIALS AND METHODS: The relative fluorouracil and FBAL F-19 signal intensity increases due to extracellular and hepatobiliary paramagnetic contrast media were evaluated in ACI rats with transplanted Morris hepatoma. Control rats (n = 6) did not receive contrast medium; study rats received gadopentetate dimeglumine (n = 6) or gadoxetic acid (n = 6) before intravenous fluorouracil administration. The biodistributions of fluorouracil and FBAL were mapped at metabolic F-19 MR imaging at about 6 minutes (early distribution phase) and 64 minutes (metabolic phase), respectively, after drug administration. RESULTS: Gadopentetate dimeglumine induced a significant (P < .05) increase in the signal intensity of fluorouracil (70%) in the hepatoma; gadoxetic acid induced a significant increase in the si...

  • Pharmacokinetic Analysis of 5-[18F]Fluorouracil Tissue Concentrations Measured with Positron Emission Tomography in Patients with Liver Metastases from Colorectal Adenocarcinoma
    Cancer research, 1997
    Co-Authors: Jutta Kissel, M.e. Bellemann, U. Haberkorn, Gunnar Brix, Ludwig G. Strauss, Antonia Dimitrakopoulou-strauss, Rüdiger E. Port, Walter J. Lorenz
    Abstract:

    The purpose of our study was to develop a pharmacokinetic model to quantify the intracellular 5-fluorouracil (5-FU) concentration in liver metastases, which is expected to be closely correlated to therapy response. In addition, the influence of the biomodulator folinic acid on the action of 5-FU in the metastases was investigated. After i.v. application of 5-FU labeled with the positron emitter fluorine-18 (5-[18F]FU), the kinetics of the regional 5-[18F]FU/uptake was measured dynamically with positron emission tomography over 120 min in 14 patients with a total of 27 liver metastases from colorectal adenocarcinoma. Activity-time curves were evaluated in the metastases, the normal liver tissue, as well as in the aorta and analyzed by a six-compartment model. The catabolic breakdown of 5-FU to Alpha-Fluoro-Beta-Alanine (FBAL) in the normal liver tissue was modeled to separate the catabolites from the cytostatic agent 5-[18F]FU and the active 5-[18F]fluorodeoxyuridine nucleotides. With our model, all measured activity-time courses could be described adequately with only small interindividual variations in parameters connected with liver and blood. Extrahepatic clearance of 5-FU was estimated as 0.66 +/- 0.33 liters/min, whereas the hepatic clearance was 0.52 +/- 0.25 liters/min. The Michaelis-Menten parameters describing the nonlinear conversion of 5-FU to FBAL were Km = 11.3 +/- 6.4 micromol and Vmax = 147.1 +/- 130.7 micromol/min. The maximum FBAL concentration in the liver was reached between 35 and 65 min after i.v. 5-FU infusion. The most sensitive parameters for therapy monitoring were k(in) and k(out), which characterize the transport in and out of the intracellular volume of the metastases, respectively. Tumor response can only be expected if k(in) is high and k(out) is low ("trapping"). These criteria were met by 6 of the 27 metastases, which were identical to those with high values for the area under the intracellular 5-FU concentration curve (AUC[meta,IC]5-FU). The parameters k(in) and k(out) were also used to investigate the influence of the biomodulating agent folinic acid on drug effect. Five of the six metastases that showed trapping belonged to patients who received folinic acid. With the exception of one patient, however, all patients who received folinic acid had multiple metastases, of which only one was able to trap 5-FU. Because patient response can only be expected when all metastases trap 5-FU, folinic acid showed no effect on the overall clinical response. With the quantitative modeling approach used, trapping of 5-FU can be assessed noninvasively and on an individual basis. This makes it possible to adjust the dose for each individual patient to optimize the treatment schedule.

  • Assessment of the biodistribution and metabolism of 5-fluorouracil as monitored by 18F PET and 19F MRI: A comparative animal study
    Nuclear medicine and biology, 1996
    Co-Authors: Gunnar Brix, M.e. Bellemann, U. Haberkorn, Ludwig Gerlach, Walter J. Lorenz
    Abstract:

    The effective clinical use of the anticancer drug 5-fluorouracil (5-FU) requires the non-invasive assessment of its transport and metabolism, particularly in the tumor and the liver, where the drug is catabolized to Alpha-Fluoro-Beta-Alanine (FBAL). In this study, the potentials and limitations of dynamic 18F PET and metabolic 19F MRI examinations for noninvasive 5-FU monitoring were investigated in ACI and Buffalo rats with transplanted MH3924A and TC5123 Morris hepatomas, respectively. Selective 5-[19F]FU and [19F]FBAL MR images were acquired 5 and 70 min after 5-FU injection using a CHESS MRI sequence. After administration of 5-[18F]FU, the kinetics of the regional 5-[18F]FU uptake were measured by dynamic PET scanning over 120 min. To allow a comparison between PET and MRI data, standardized uptake values (SUV) were computed at the same points in time. The TC5123 hepatoma showed a significantly (p < 0.002) higher mean SUV at 5 and 70 min post-5-FU injection than the MH3924A cell lines, whereas there were no significant differences between the mean SUV measured in the liver of both animal populations. In contrast to the PET data, no significant differences in the mean 5-[19F]FU and [19F]FBAL MR signal values in the tumor of both models were observed. The MR images, however, yielded the additional information that 5-FU is converted to FBAL only in the liver and not in the hepatomas.

Robert Martino - One of the best experts on this subject based on the ideXlab platform.

  • Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs.
    Clinica chimica acta; international journal of clinical chemistry, 2005
    Co-Authors: Myriam Malet-martino, Véronique Gilard, Franck Desmoulin, Robert Martino
    Abstract:

    Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy provides a highly specific tool for the detection, identification and quantification of fluorine-containing drugs and their metabolites in biofluids. The value and difficulties encountered in investigations on drug metabolism are first discussed. Then the metabolism of three fluoropyrimidines in clinical use, 5-fluorouracil, 5-fluorocytosine and capecitabine are reported. Besides the parent drug and the already known fluorinated metabolites, 12 new metabolites were identified for the first time with 19F NMR in human biofluids. Nine of them can only be observed with this technique: fluoride ion, N-carboxy-Alpha-Fluoro-Beta-Alanine, Alpha-Fluoro-Beta-Alanine conjugate with deoxycholic acid, 2-fluoro-3-hydroxypropanoic acid, fluoroacetic acid, O2-beta-glucuronide of fluorocytosine, fluoroacetaldehyde hydrate and its adduct with urea, fluoromalonic acid semi-aldehyde adducts with urea. This emphasizes the high analytical potential of 19F NMR for the furtherance in the understanding of fluoropyrimidine catabolic pathways. 19F NMR should also play a role in the therapeutic monitoring of FU and its prodrugs in specific groups of patients, e.g. hemodialyzed patients or patients with deficiency in FU catabolic enzymes.

  • the anti cancer drug 5 fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate
    British Journal of Cancer, 1998
    Co-Authors: M Arellano, Robert Martino, M C Maletmartino, P Gires
    Abstract:

    We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of Alpha-Fluoro-Beta-Alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.

  • 19F Nuclear Magnetic Resonance Analysis of 5-Fluorouracil Metabolism in Four Differently Pigmented Strains of Nectria haematococca
    Applied and environmental microbiology, 1991
    Co-Authors: Denise Parisot, Robert Martino, M. C. Malet-martino, P Crasnier
    Abstract:

    F nuclear magnetic resonance spectroscopy was used to study the metabolism of 5-fluorouracil in four strains of Nectria haematococca which displayed similar sensitivities to growth inhibition by this compound but differed in their pigmentation. The major metabolites, 5-fluorouridine and Alpha-Fluoro-Beta-Alanine, were excreted into the medium by all four strains. The classical ribofluoronucleotides (5-fluorouridine-5'-monophosphate, -diphosphate, and -triphosphate) and Alpha-Fluoro-Beta-Alanine were identified in the acid-soluble fraction of perchloric acid extracts of mycelia. Two hydrolysis products of 5-fluorouracil incorporated into RNA were found in the acid-insoluble pool. They were unambiguously assigned to 5-fluorouridine-2'-monophosphate and 3'-monophosphate with specific hydrolysis reactions on isolated RNA. The lack of fluorodeoxyribonucleotides and the fact that the four strains incorporated similar amounts of fluororibonucleotides into their RNAs strongly suggest an RNA-directed mechanism of cytotoxicity for 5-fluorouracil. The heavily pigmented wild type differed from the three low-pigmented strains in its low uptake of 5-fluorouracil and, consequently, in its reduced biosynthesis of 5-fluorouridine and Alpha-Fluoro-Beta-Alanine. At present, it is not clear whether this change in 5-fluorouracil metabolism is a side effect of pigment production or results from another event.

M.e. Bellemann - One of the best experts on this subject based on the ideXlab platform.

  • Biochemical modulation of the catabolism and tissue uptake of the anticancer drug 5-fluorouracil by 5-bromovinyluracil: Assessment with metabolic 19F MR imaging
    Magnetic resonance in medicine, 1999
    Co-Authors: Gunnar Brix, M.e. Bellemann, U. Haberkorn
    Abstract:

    Using chemical shift-selective (19)F magnetic resonance (MR) imaging, we investigated the biomodulating action of 5-bromovinyluracil (BVU) on the degradation of the anticancer drug 5-fluorouracil (5-FU) to its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) and the tissue uptake of 5-FU in ACI rats with transplanted Morris hepatoma. Rats in the control group (n = 7) received 200 mg/kg body weight of 5-FU intravenously, whereas the rats in the BVU group (n = 7) additionally received 30 mg/kg body weight of BVU intraperitoneally about 45 min before 5-FU injection. In each animal examination, three selective (19)F MR images were acquired sequentially after 5-FU administration with an acquisition time of 32 min each: an early 5-FU image (dominant Fourier line, 8 min p.i.) that characterized the early uptake of the drug into the various tissues, an FBAL image (dominant Fourier line, 56 min p.i.) that reflected the catabolism of the drug, and a late 5-FU image (dominant Fourier line, 78 min p.i.) that assessed the retention ("trapping") of unmetabolized 5-FU and its MR-visible anabolites. Pretreatment with BVU resulted in a highly statistical significant decrease (P 0.7). Moreover, our results indicate that 5-FU tumor uptake is not only dependent on the plasma concentration of unmetabolized 5-FU but is also determined by tumor-specific factors, these showing considerable variations between individual neoplasms. Magn Reson Med 42:936-943, 1999.

  • Direct detection of intratumoral 5-fluorouracil trapping using metabolic 19F MR imaging.
    Magnetic resonance imaging, 1999
    Co-Authors: Gunnar Brix, M.e. Bellemann, Ludwig Gerlach, U. Haberkorn
    Abstract:

    The effective use of 5-fluorouracil (5-FU) in cancer therapy requires the noninvasive assessment of its transport, metabolism, and retention ("trapping") in the different tissues of the organism, particularly in the tumor. We used a chemical-shift selective 19F magnetic resonance (MR) imaging technique to map selectively 5-FU and its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) in six ACI rats bearing Morris hepatoma. After i.v. administration of 200 mg/kg-bw 5-FU, three metabolic MR maps were acquired consecutively in each animal: 1) an early 5-FU image (5-37 min post-injection (p.i.); dominant Fourier line, 8 min p.i.) characterizing the early uptake of 5-FU into the various tissues; 2) an FBAL image (40-72 min p.i.; dominant Fourier line, 56 min p.i.) reflecting the catabolism of the drug; and 3) a late 5-FU image (75-107 min p.i.; dominant Fourier line, 78 min p.i.) to assess the retention of unmetabolized 5-FU and its MR-visible anabolites. In the early 5-FU maps, the drug was detected in all major organs (e.g., heart, liver, kidneys) as well as in the muscular system. The FBAL maps showed no FBAL accumulation in the hepatoma which reveals that the tumor cells have lost hepatocellular functions relevant for 5-FU catabolism. On the late 5-FU maps, a significant amount of 5-FU was detected in only one of the six Morris hepatomas. The observation in this rat verifies directly that 5-FU can be trapped in solid tumors. The images, moreover, emphasize the necessity of acquiring spatially-resolved MR data to detect metabolic tumor heterogeneity.

  • Intra- and extracellular fluorouracil uptake: assessment with contrast-enhanced metabolic F-19 MR imaging.
    Radiology, 1998
    Co-Authors: Gunnar Brix, M.e. Bellemann, Ludwig Gerlach, U. Haberkorn
    Abstract:

    PURPOSE: To assess the extra- and intracellular uptake of the anticancer drug fluorouracil and its major catabolite Alpha-Fluoro-Beta-Alanine (FBAL) at gadolinium-enhanced fluorine-19 magnetic resonance (MR) imaging. MATERIALS AND METHODS: The relative fluorouracil and FBAL F-19 signal intensity increases due to extracellular and hepatobiliary paramagnetic contrast media were evaluated in ACI rats with transplanted Morris hepatoma. Control rats (n = 6) did not receive contrast medium; study rats received gadopentetate dimeglumine (n = 6) or gadoxetic acid (n = 6) before intravenous fluorouracil administration. The biodistributions of fluorouracil and FBAL were mapped at metabolic F-19 MR imaging at about 6 minutes (early distribution phase) and 64 minutes (metabolic phase), respectively, after drug administration. RESULTS: Gadopentetate dimeglumine induced a significant (P < .05) increase in the signal intensity of fluorouracil (70%) in the hepatoma; gadoxetic acid induced a significant increase in the si...

  • Pharmacokinetic Analysis of 5-[18F]Fluorouracil Tissue Concentrations Measured with Positron Emission Tomography in Patients with Liver Metastases from Colorectal Adenocarcinoma
    Cancer research, 1997
    Co-Authors: Jutta Kissel, M.e. Bellemann, U. Haberkorn, Gunnar Brix, Ludwig G. Strauss, Antonia Dimitrakopoulou-strauss, Rüdiger E. Port, Walter J. Lorenz
    Abstract:

    The purpose of our study was to develop a pharmacokinetic model to quantify the intracellular 5-fluorouracil (5-FU) concentration in liver metastases, which is expected to be closely correlated to therapy response. In addition, the influence of the biomodulator folinic acid on the action of 5-FU in the metastases was investigated. After i.v. application of 5-FU labeled with the positron emitter fluorine-18 (5-[18F]FU), the kinetics of the regional 5-[18F]FU/uptake was measured dynamically with positron emission tomography over 120 min in 14 patients with a total of 27 liver metastases from colorectal adenocarcinoma. Activity-time curves were evaluated in the metastases, the normal liver tissue, as well as in the aorta and analyzed by a six-compartment model. The catabolic breakdown of 5-FU to Alpha-Fluoro-Beta-Alanine (FBAL) in the normal liver tissue was modeled to separate the catabolites from the cytostatic agent 5-[18F]FU and the active 5-[18F]fluorodeoxyuridine nucleotides. With our model, all measured activity-time courses could be described adequately with only small interindividual variations in parameters connected with liver and blood. Extrahepatic clearance of 5-FU was estimated as 0.66 +/- 0.33 liters/min, whereas the hepatic clearance was 0.52 +/- 0.25 liters/min. The Michaelis-Menten parameters describing the nonlinear conversion of 5-FU to FBAL were Km = 11.3 +/- 6.4 micromol and Vmax = 147.1 +/- 130.7 micromol/min. The maximum FBAL concentration in the liver was reached between 35 and 65 min after i.v. 5-FU infusion. The most sensitive parameters for therapy monitoring were k(in) and k(out), which characterize the transport in and out of the intracellular volume of the metastases, respectively. Tumor response can only be expected if k(in) is high and k(out) is low ("trapping"). These criteria were met by 6 of the 27 metastases, which were identical to those with high values for the area under the intracellular 5-FU concentration curve (AUC[meta,IC]5-FU). The parameters k(in) and k(out) were also used to investigate the influence of the biomodulating agent folinic acid on drug effect. Five of the six metastases that showed trapping belonged to patients who received folinic acid. With the exception of one patient, however, all patients who received folinic acid had multiple metastases, of which only one was able to trap 5-FU. Because patient response can only be expected when all metastases trap 5-FU, folinic acid showed no effect on the overall clinical response. With the quantitative modeling approach used, trapping of 5-FU can be assessed noninvasively and on an individual basis. This makes it possible to adjust the dose for each individual patient to optimize the treatment schedule.

  • Assessment of the biodistribution and metabolism of 5-fluorouracil as monitored by 18F PET and 19F MRI: A comparative animal study
    Nuclear medicine and biology, 1996
    Co-Authors: Gunnar Brix, M.e. Bellemann, U. Haberkorn, Ludwig Gerlach, Walter J. Lorenz
    Abstract:

    The effective clinical use of the anticancer drug 5-fluorouracil (5-FU) requires the non-invasive assessment of its transport and metabolism, particularly in the tumor and the liver, where the drug is catabolized to Alpha-Fluoro-Beta-Alanine (FBAL). In this study, the potentials and limitations of dynamic 18F PET and metabolic 19F MRI examinations for noninvasive 5-FU monitoring were investigated in ACI and Buffalo rats with transplanted MH3924A and TC5123 Morris hepatomas, respectively. Selective 5-[19F]FU and [19F]FBAL MR images were acquired 5 and 70 min after 5-FU injection using a CHESS MRI sequence. After administration of 5-[18F]FU, the kinetics of the regional 5-[18F]FU uptake were measured by dynamic PET scanning over 120 min. To allow a comparison between PET and MRI data, standardized uptake values (SUV) were computed at the same points in time. The TC5123 hepatoma showed a significantly (p < 0.002) higher mean SUV at 5 and 70 min post-5-FU injection than the MH3924A cell lines, whereas there were no significant differences between the mean SUV measured in the liver of both animal populations. In contrast to the PET data, no significant differences in the mean 5-[19F]FU and [19F]FBAL MR signal values in the tumor of both models were observed. The MR images, however, yielded the additional information that 5-FU is converted to FBAL only in the liver and not in the hepatomas.

Manabu Muto - One of the best experts on this subject based on the ideXlab platform.

  • Accumulation of Alpha-Fluoro-Beta-Alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Yoshitaka Nishikawa, Taro Funakoshi, Takahiro Horimatsu, Shin’ichi Miyamoto, Takeshi Matsubara, Motoko Yanagita, Shunsaku Nakagawa, Atsushi Yonezawa, Kazuo Matsubara, Manabu Muto
    Abstract:

    Purpose High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD). Methods We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry. Results The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum Alpha-Fluoro-Beta-Alanine (FBAL, 59.2 µg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureidopropionic acid were not changed. Conclusion We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.

  • accumulation of alpha fluoro beta alanine and fluoro mono acetate in a patient with 5 fluorouracil associated hyperammonemia
    Cancer Chemotherapy and Pharmacology, 2017
    Co-Authors: Yoshitaka Nishikawa, Taro Funakoshi, Takahiro Horimatsu, Takeshi Matsubara, Motoko Yanagita, Shunsaku Nakagawa, Atsushi Yonezawa, Kazuo Matsubara, Shinichi Miyamoto, Manabu Muto
    Abstract:

    Purpose High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD).