A Comparative Study on the Uptake and Incorporation of Radiolabeled Methionine, Choline and Fluorodeoxyglucose in Human Astrocytoma

doi:10.1016/S1536-1632(01)00010-5

Molecular Imaging & Biology

Volume 4, Issue 2, March–April 2002, Pages 147-156

https://doi.org/10.1016/S1536-1632(01)00010-5 Get rights and content

Abstract

Purpose: The goal of this investigation was to evaluate uptake and incorporation of 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG), ¹¹C-methionine, and ¹¹C-choline in 17 patients suspected of grade-II and grade-III tumors using positron emission tomography (PET) and use in vitro astrocytoma cell lines in order to support in vivo findings.

Methods: Seventeen patients with suspected astrocytomas (9 grade-II and 8 grade-III) were studied by PET with FDG and ¹¹C-methionine; and one patient (grade-III) with FDG, ¹¹C-methionine and ¹¹C-choline. Uptake of PET molecular imaging probe was quantitative based on tumor to corresponding contralateral-region uptake ratio, tumor to mean-cortical-uptake ratio, and tumor to white matter uptake ratio. This was correlated with World Health Organization histology grading system and clinical follow-up. Uptake and incorporation of ³H-methionine, ³H-choline and FDG into lipid, RNA, DNA, and protein were investigated in a grade-III human tumor brain-14 astrocytoma cell line.

Results: A time-dependent increase in the total uptake of ³H-methionine, ³H-choline and FDG was observed in human tumor brain-14 astrocytoma-III cell line. ³H-methionine was incorporated predominantly into proteins (in excess of 40% at 1 h) while ³H-choline incorporated primarily into lipids (in excess of 60% at 1hr). Total uptake of FDG was accounted for in the free-pool supernatant fraction. In all patients, PET images of ¹¹C-methionine and FDG provided higher tumor to white matter ratios than tumor to corresponding contra-lateral region ratios and tumor to mean cortical uptake ratios. In grade II patients, FDG did not exhibit significant increase in tumor uptake, while ¹¹C-methionine was a good predictor with ratios of approximately 1.50 ± 0.48. In grade III patients, both FDG and ¹¹C-methionine exhibited higher ratios than for grade II, with ¹¹C-methionine being the greatest (ratios of 2.50 ± 0.85), possibly suggesting enhanced protein synthesis. With respect to tumor delineating potential, ¹¹C-choline may be equal to or slightly better than ¹¹C-methionine in the subject evaluated with all three probes.

Conclusions: Results suggest that a combination of FDG and ¹¹C-methionine is useful in the prediction of histological grade of astrocytomas. In addition, ¹¹C-methionine is better than FDG in delineating tumor boundary for low-grade gliomas. In vitro results suggest that ³H-methionine is significantly incorporated into proteins and provides the major driving force in the uptake of ¹¹C-methionine observed in PET images. (Mol Imag Biol 2002;4:147–156)

Introduction

Clinical PET investigations with radiolabeled 2- deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) and L–me thyl ¹¹C-methionine have been widely used in tumor diagnosis and evaluation of treatment effectiveness.1, 2 Comparative investigations of these probes have been largely directed towards brain tumors due to the enormous complexity in diagnosis.3, 4 Investigations with FDG have been successful in imaging higher grade brain tumors; but in the case of low grade brain tumors, findings have been mixed due to difficulties in differentiation from surrounding tissues.5, 6, 7 Several reports have also observed high FDG uptake in a variety of inflammatory lesions.8, 9 Even within tumors, about 24% of the FDG concentration in the tumor mass may actually be in macrophages and other inflammatory cells.⁹

In order to gain additional insights into tumor biology using positron emission tomography (PET), several PET centers are now using radiolabeled methionine and choline in an effort to complement FDG in the diagnosis of brain tumors.10, 11, 12, 13 The uptake of ¹¹C- methionine in malignant tissue is thought to reflect increased active amino acid transport and protein synthesis, but the exact metabolic fate of ¹¹C-methionine in the brain in vivo may be more complex.14, 15, 16, 17, 18 While many reports suggest incorporation of ¹¹C-methionine into proteins,14, 15 a few have suggested tissue accumulation of ¹¹C-methionine by transport.¹⁶ Carbon-11 methionine is also incorporated into the lipid fraction and nucleic acid by transmethylation via S-adenosyl-L-methionine.¹⁷ Recent inquiries have also suggested that tissue accumulation of ¹¹C-methionine may be independent of blood brain barrier disruption.¹⁹ Significant uptake of ¹¹C-methionine has also been reported in cases that have not been diagnosed as malignancy.²⁰ Therefore, like FDG, there are still some unanswered questions on mechanisms of ¹¹C-methionine accumulation.

In addition to FDG and ¹¹C-methionine investigations on these patients, the potential of ¹¹C-choline in demarcating brain tumors is now also being investigated.12, 21 Recent work has shown the usefulness of ¹¹C-choline in the diagnosis of brain tumors and tumors in the pelvic region, particularly prostate cancer.12, 13, 22 Choline is a quaternary ammonium base, utilized for the biosynthesis of phosphatidylcholine (lecithin), an essential component of cell membranes.²³ Cytidine-5′-diphosphocholine (CDP choline) and phosphorylcholine are key intermediates in the biosynthesis of phospholipids. Malignant transformation of cells is associated with induction of choline kinase activity resulting in increased levels of phosphorylcholine. This leads to increased membrane turnover and enhanced cell proliferation.²⁴ Investigations using ³¹P-magnetic resonance spectroscopy, in vivo and in vitro have shown that rapidly proliferating tumors contain large amounts of phospha- tidylcholine and phosphorylcholine.25, 26

In an effort to understand and correlate the diagnostic potential of FDG, ¹¹C-methionine and ¹¹C-choline, the goal of this investigation was to evaluate a subset of brain tumors in patients suspected of grade II and grade III astrocytomas. The PET images were visually and quantitatively analyzed for the relative uptake of FDG and ¹¹C-methionine in the two different grades. Due to the ambiguity in the biochemical fate of ¹¹C- methionine in various tumors, in vitro cell line determinations were performed. In vitro determinations with a grade III human tumor brain-14 human astrocytoma cell line were carried out using ³H-methionine, ³H-choline and FDG in order to verify observations in PET investigations regarding uptake and incorporation of FDG, ¹¹C-methionine and ¹¹C-choline into proteins, lipids, RNA and DNA.

Section snippets

Materials and Methods

The human tumor brain—14 astrocytoma cell line was obtained from American Type Culture Collection (Manassas, VA, USA). The cell line was maintained in Eagle's Minimal Essential medium with Earle's BSS and 2 mM L-glutamine, 1.0 mM sodium pyruvate, 0.1 mM nonessential amino acids fortified with 10% fetal calf serum in a humidified atmosphere at 37°C with 5% CO₂. All other chemicals used were of analytical grade (Sigma, St. Louis, MO, USA). Tissue culture medium and fetal calf serum were obtained

PET Determinations

The uptake of FDG and ¹¹C-methionine in a grade II astrocytoma patient is shown in Figure 1. Uptake of FDG was not high in the tumor and boundaries were difficult to demarcate. This is probably due to the significant uptake of FDG in the surrounding tissues. On the other hand, ¹¹C-methionine uptake was clearly visible and allowed demarcation of the boundaries. Data for both FDG and ¹¹C-methionine determinations are presented in Table 1 for grade-II patients, in accordance with the World Health

Discussion

Several recent investigations have attempted to correlate metabolic differences in FDG and ¹¹C-methionine uptake in brain tumors. Derlon et al.6, 31 included patients with astrocytomas and oligodendrogliomas and found glucose hypometabolism in the tumor similar to normal white matter. They reported a good correlation between ¹¹C-methionine uptake in the region with histological grading. Bustany et al.³² investigated protein synthesis rate using a three-compartment model in 14 patients with

Conclusion

This work with astrocytomas suggests that ¹¹C-methionine is better than FDG in delineating tumor location for low-grade gliomas. A combination of FDG and ¹¹C-methionine is useful in the analysis of grade II and III astrocytomas. Tumor to white matter ratios (≥1.5) of FDG provide higher (75%) and relatively lower (67%) sensitivity for grade-III and grade-II tumor detection, respectively. The in vitro results suggest that a significant amount of ³H-methionine is incorporated into proteins. Thus,

Acknowledgements

The authors thank Dr. James Olson, Department of Biochemistry, Wright State University for the access to his tissue culture facility and Dr. Nicholas Reo, Department of Biochemistry, Wright State University for the use of his laboratory facilities. This work was supported by grants-in-aid (SP-6086) from Wallace Kettering Neuroscience Institute.

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Original articleA Comparative Study on the Uptake and Incorporation of Radiolabeled Methionine, Choline and Fluorodeoxyglucose in Human Astrocytoma☆

Abstract

Introduction

Section snippets

Materials and Methods

PET Determinations

Discussion

Conclusion

Acknowledgements

Uptake of carbon-11-methionine and fluorodeoxyglucose in Non-Hodgkin's lymphomaA PET study

J. Nucl. Med.

Clinical Value of PET with 18F- Fluorodeoxyglucose and L-Methyl-11C- Methionine for Diagnosis of Recurrent Brain Tumor and Radiation Injury

Acta. Radiologica.

Clinical Positron Emission Tomography for Brain TumorsComparison of Fluorodeoxyglucose F-18 and L-Methyl-11C-methionine

Am. J. Neuroradiol.

Regional Methionine and Glucose Uptake in High-Grade GliomasA comparative Study on PET-Guided Sterotactic Biopsy

J. Nucl. Med.

Preoperative Evaluation of 54 Gliomas by PET with Fluorine-18-Fluorodeoxyglucose and/or C-11 Methionine

J. Nucl. Med.

The in vivo Metabolic Pattern of Low-grade Brain GliomasA Positron Emission Tomographic Study Using 18F-fluorodeoxyglucose and 11C-L-methylmethionine

Neurosurgery

Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy

Eur. J. Nucl. Med.

Microautoradiographic Study for the Differentiation of Intratumoral Macrophages, Granulation Tissues and Cancer Cells by the Dynamics of Fluorine-18-fluorodeoxyglucose Uptake

J. Nucl. Med.

High Accumulation of Fluorine-18-fluorodeoxyglucose in turpentine-induced inflammatory tissue

J. Nucl. Med.

Concurrent FDG and methionine study of brain tumors

J. Nucl. Med.

PET imaging of brain tumor with methyl-11C-choline.

J. Nucl. Med.

Comparative study of radiolabeled fluorodeoxyglucose, methionine and choline in human astrocytoma

J. Nucl. Med.

Brain tumorsdetection with C-11 choline PET

Radiology

In vivo kinetic model with L-(35S) methionine for the determination of local cerebral rates for methionine incorporation into protein in the rat.

J. Neurochem.

Methionine Uptake by Tumor TissueA Microautoradiographic Comparison with FDG

J. Nucl. Med.

Re-evaluation of amino acid PET studiesCan the protein synthesis rates in brain and tumor tissue be measured in vivo?

J. Nucl. Med.

Increased amino acid transport into brain tumors measured by PET of L-(2–18F)fluorotyrosine

J. Nucl. Med.

Amino acid uptake in iscemically compromised brain tissue

Stroke

Original article
A Comparative Study on the Uptake and Incorporation of Radiolabeled Methionine, Choline and Fluorodeoxyglucose in Human Astrocytoma☆

The in vivo Metabolic Pattern of Low-grade Brain GliomasA Positron Emission Tomographic Study Using ¹⁸F-fluorodeoxyglucose and ¹¹C-L-methylmethionine