Preferential uptake of zinc, manganese, and rubidium in rat brain tumor

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Abstract

The search for radionuclides that can be an index of viability in proliferating cells is important for nuclear medicine diagnosis of brain tumors. On the basis of the finding that 65Zn is preferentially taken up in rat brain tumors, the uptake of various radionuclides was examined in rat brain tumor by using the multitracer technique. Male Fisher rats were intrahippocampally injected with C6 glioma cells. Fourteen days after implantation, the radioactive multitracer solution was injected into the tail vein of tumor-bearing rats. One hour after intravenous injection, the uptake of 65Zn, 83Rb and 54Mn was relatively high in C6 glioma of 15 radionuclides detected, and was much higher than in other brain regions and in the blood. It is likely that rubidium and manganese, in addition to zinc, are preferentially taken up by tumors in the brain.

Introduction

Noninvasive nuclear medicine techniques are important for the diagnosis of brain tumors [10]. 18F-fluorodeoxyglucose (FDG) positron emission tomoghaphy (PET) is widely used for the diagnosis of brain tumors; 18F-FDG uptake in primary brain tumors is related to the histopathological grade and is a good predictor of prognosis [1], [6], [7], [8], [9]. 18F-FDG PET is also useful for differential diagnosis between recurrence and radiation necrosis after treatment. 18F-FDG PET often fails to detect brain tumors, however, because of the relatively high uptake of 18F-FDG in normal brain tissue, in which glucose is actively used [12]. Therefore, the development of a tumor-specific imaging agent is necessary for an advanced diagnosis of brain tumors and also for effective therapy.

The uptake of zinc, an essential transition metal for animals and human, is critical for cell proliferation, because zinc is necessary for DNA replication and transcription, and protein synthesis [17]. On the basis of the idea that zinc uptake can be an index of viability in proliferating cells, brain tumor imaging with 65Zn was performed using autoradiography. 65Zn uptake in the brain tumors was approximately 10 times higher than in other brain regions, suggesting great potential for the use of 69mZn, a short half-life γ emitter, in the diagnosis of brain tumors [16]. Brain tumors might be positively imaged with other essential transition metals because of slow turnover of transition metals in the brain.

The multitracer technique was developed at RIKEN [2], [3]; a large number of radionuclides, which cover most elements of the periodic table, are produced by irradiation of different targets, such as silver and gold foil, with high-energy heavy ions. The nuclear reactions induced by the heavy ions result in simultaneous production of a large number of radionuclides. The multitracer technique has the merit that the radionuclides obtained are carrier-free. Biological studies on the metabolism of various elements in normal and disease model animals have been carried out using the multitracer technique. The technique also has the advantage that the metabolism of various elements can be determined under strictly identical conditions. Thus, the multitracer technique was applied to determine the uptake of various radionuclides in rat brain tumor.

The aim of the present study is to find elements that have selective affinity for brain tumors, and to estimate whether the uptake of the elements can be an index of viability in proliferating cells.

Section snippets

Cell culture

C6 glioma cells were maintained in minimum essential medium (MEM, Nissui Pharmaceutical Co., Ltd, Tokyo, Japan) containing 10% heat-inactivated fetal bovine serum and streptomycin (100 μg/mL) in a humidified atmosphere of 5% CO2 and 95% air at 37°C.

Multitracer solution

A silver foil target was irradiated for approximately 20 h with a 135 MeV/nucleon 14N beam from the RIKEN Ring Cyclotron [2], [3]. The silver target containing a large number of radionuclides was dissolved in nitric acid after irradiation.

Results

When the multitracer solution was intravenously injected into C6 glioma-bearing rats, 15 radionuclides, i.e., 7Be, 22Na, 46Sc, 48V, 51Cr, 54Mn, 56Co, 65Zn, 75Se, 83Rb, 85Sr, 88Zr, 95mTc, 99Rh, and 103Ru, were detected in the brain tissues and/or blood 1 h after injection.

The uptake of 22Na, 65Zn, 83Rb, and 54Mn was high in the tumor (0.5–0.8% dose/g) (Fig. 1). The uptake of 65Zn and 83Rb in the tumor was approximately 10 times higher than in any other brain region. The uptake of 54Mn in the

Discussion

Various nutrients are supplied to the brain parenchyma across the blood-brain and the blood-cerebrospinal fluid barriers. Zinc is a critical nutrient for brain functions. However, zinc transport is tightly controled by the brain barrier systems [15]. Angiogenesis is characteristic of tumors, including brain tumors, for acquisition of nutrients. The blood-brain barrier does not usually exist in brain tumors [14]. There is the possibility that brain tumors are positively imaged with radioactive

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