The uptake of zinc, an essential nutrient, is critical for cell proliferation. On the basis of the idea that zinc uptake can be an index of viability in proliferating cells, tumor imaging with 65Zn was performed using autoradiography. After s.c. implantation of ascites hepatoma (AH7974F) cells into the dorsum, 1 h after i.v. injection of 65ZnCl2, 65Zn uptake in the tumor was higher than in the brain tissue but lower than in the liver, which suggests that brain tumors can be positively imaged with 65Zn. After implantation of AH7974F cells into the periaqueductal gray, 1 h after i.v. injection of 65ZnCl2, 65Zn uptake in the tumor was ∼10 times higher than in other brain regions. After implantation of C6 glioma cells into the hippocampus, 65Zn uptake in the tumor was also much higher than in other brain regions. The present findings demonstrate that brain tumors can be imaged with radioactive zinc. To compare brain tumor imaging with 65Zn with that of [18F]fluorodeoxyglucose (FDG), which is widely used for the diagnosis of brain tumors, 14C-FDG imaging of the C6 glioma was performed in the same manner. 14C-FDG uptake in the tumor was ∼1.5 times higher than in the contralateral region in which 14C-FDG uptake was relatively high. It is likely that zinc uptake is more specific for brain tumors than is FDG uptake, which suggests that there is great potential for the use of 69mZn, a short half-life γ emitter, in the diagnosis of brain tumors.

Noninvasive nuclear medicine techniques are important for the diagnosis of brain tumors. Unlike morphological imaging, such as X-ray CT,2 and magnetic resonance imaging, nuclear medicine techniques can detect tumors by imaging biochemical and metabolic changes of tumors (1). [18F]FDG PET is widely used for the diagnosis of brain tumors (2, 3, 4, 5); [18F]FDG uptake in primary brain tumors is related to the histopathological grade and is a good predictor of prognosis. [18F]FDG PET is also useful for differential diagnosis between recurrence and radiation necrosis after treatment (6, 7, 8, 9, 10). [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 (11). Therefore, the development of a tumor-specific imaging agent is necessary for an advanced diagnosis of brain tumors and also for effective therapy.

Zinc, an essential transition metal for animals and humans, has three functions in zinc metalloproteins, i.e., catalytic, coactive (or cocatalytic), and structural (12). Zinc is necessary for DNA replication and transcription, and protein synthesis. Numerous zinc enzymes and proteins are associated with the metabolism of proteins, nucleic acids, carbohydrates, and lipids. This metal has critical roles in the regulation of proliferation and differentiation of cells. Thus, dietary zinc deprivation powerfully retards the growth of humans and animals (13).

Zinc is also involved in the metabolism and interaction of tumor cells. Dietary zinc deprivation effectively suppresses the proliferation of transplanted tumors in tumor-bearing animals (14, 15, 16, 17, 18). Fong et al.(19) demonstrated that dietary zinc deprivation enhances the carcinogenic effects of methylbenzylnitrosamine. Dimethylbenz[a]anthracene-induced carcinoma is inhibited by dietary zinc loading (20). The response of neoplastic tumors to zinc deficiency indicates a potential for therapeutic opportunities, although there is no known role for zinc in oncogenesis (21). On the other hand, zinc metabolism in tumor cells may be associated with their malignancy. Both normal and malignant cells secrete matrix metalloproteinases, which are important for invasion and metastases. The amount of the enzymes secreted by malignant cells is reported to exceed that of normal cells (22). In tumor cells, the functions of zinc are closely related to metastasis and proliferation. Thus, zinc uptake appears to be an index of tumor viability. When tumors are imaged with radioactive zinc, the information obtained is considered to be unique and important for diagnosis and therapy.

In the present paper, imaging of 65Zn uptake in tumors was examined using autoradiography. Brain tumors may be positively imaged with 65Zn because of the slow turnover of zinc in the brain (23, 24).

Chemicals.

65ZnCl2 [85.1 MBq (2.30 mCi)/mg] in 0.5 n HCl and 14C-FDG [11.1 GBq (300 mCi)/mm] in saline were obtained from NEN Life Science Products, Inc. (Boston, MA) and American Radiolabeled Chemicals Inc. (St. Louis, MO), respectively.

Cell Culture.

Ascites hepatoma 7974F (AH7974F cells), originally obtained from a hepatoma induced with 4-dimethylaminoazobenzene, were maintained in DMEM (Nissui Pharmaceutical Co., Ltd, Tokyo, Japan) containing 10% heat-inactivated fetal bovine serum, penicillin G (100 units/ml), and streptomycin (100 μg/ml), in a humidified atmosphere of 5% CO2 and 95% air at 37°C. Astrocytoma C6, glioma cells, originally obtained from a glioma induced with N-nitrosomethylurea, were maintained in MEM (Nissui Pharmaceutical Co., Ltd), containing 10% heat-inactivated fetal bovine serum, penicillin G (100 units/ml), and streptomycin (100 μg/ml), under the conditions described above.

Experimental Animals.

Male Donryu rats (4 and 6 weeks of age) and male Fischer rats (4 and 8 weeks of age) were obtained from Japan SLC, Inc. (Hamamatsu, Japan). The animals were housed under standard laboratory conditions (23 ± 1°C, 55 ± 5% humidity). The animals had access to tap water and were fed a conventional chow diet (Oriental Yeast Co., Ltd., Yokohama, Japan) ad libitum. The lights were on from 8 a.m. to 8 p.m.. All of the experiments were performed in accordance with the Principles of Laboratory Animal Care of the NIH and University of Shizuoka.

Whole-Body Autoradiography.

Male Donryu rats (5 weeks of age) were given s.c. injections of AH7974F cells (1 × 107 cells/0.2 ml of culture media/rat) into the dorsum. Ten days after implantation, 65ZnCl2 [10 μCi/0.2 ml of 0.1 m acetate buffer (pH 4.0)/rat] was injected into the tail vein of control and tumor-bearing rats (n = 2 per group). The rats were killed under deep diethyl ether anesthesia 1 h after injection of 65ZnCl2, frozen immediately, fixed with ice-cold 8% carboxymethyl cellulose, frozen on the specimen stage at −20°C, and sliced at 100-μm thickness at −20°C with a microtome (Cryotome CR-502; Nakagawa Co., Ltd, Tokyo, Japan). The serial sagittal slices were dried in a Cryotome at −20°C. The distribution of radioactivity in each area of the selected slices was determined using autoradiography (Bio-imaging Analyzer BAS 2000; Fuji Photo Film, Tokyo, Japan) after exposure to the imaging plates (Fuji imaging plate, 20 × 40 cm; Fuji Photo Film Co. Ltd.) for 7 days.

In Vivo Distribution of 65Zn.

Four Donryu rats (5 weeks of age) were given s.c. injections of AH 7974F cells (1 × 107 cells/0.2 ml of culture media/rat) into the inguinal region. Ten days after implantation, 65ZnCl2 [4 μCi/0.2 ml 0.1 m acetate buffer (pH 4.0)/rat] was injected into the tail vain of tumor-bearing rats. One hour after the injection of 65ZnCl2, the rats were killed after collecting the blood under deep diethyl ether anesthesia. The brain and tumor were excised from the rats, weighed, and counted for the radioactivity in a gamma-counter (Packard 5530; Packard Instrument Co., Inc., Meriden, CT). Four Fischer rats (5 weeks of age) were given s.c. injections of C6 glioma cells (2 × 107 cells/0.25 ml of culture media/rat) into the inguinal region. Seven days after implantation, tumor-bearing rats were treated in the same manner as described above.

Brain Autoradiography.

Donryu rats (7 weeks of age) were anesthetized with chloral hydrate in physiological saline and placed in a stereotaxic apparatus. AH7974F cells (2 × 105/10 μl of culture media/rat) or vehicle (10 μl of culture media/rat) were injected at a rate of 0.7 μl/min into the periaqueductal gray of the rats (−4.9 mm posterior to bregma, ±0 mm lateral to the midline suture, and −5.1 mm from the dura) via a microdialysis probe without a dialyzing membrane using a microinjection pump (CMA/100; CMA Microdialysis, Solna, Sweden; 4 rats per group). Fourteen days after injection, 65ZnCl2 [20 μCi/0.3 ml of 0.1 m acetate buffer (pH 4.0)/300 g of body weight] was injected into the tail vein of the rats. The rats were killed under deep diethyl ether anesthesia 1 h after injection of 65ZnCl2. The brains were excised from the rats and frozen immediately, fixed with ice-cold 4% sodium carboxymethyl cellulose on the specimen stage, frozen at −20°C, and sliced at 300-μm thickness at −20°C with a microtome (Cryostat HM505E; Microm Laborgerate GmbH, Heidelberg, Germany). The serial coronal slices were dried in a Cryostat at −20°C. The distribution of radioactivity in each area of the slices was determined by autoradiography after exposure to the imaging plates for ∼7 days as described above. The exact time of exposure was determined by taking into account the physical decay. Radioactivity (PSL/mm2) in each area from the autoradiograms of the selected slices was measured quantitatively using a Bio-imaging analyzer and was corrected according to PSL/mm2 internal standards in each autoradiogram. There was a linear correlation between PSL/mm2 and cpm obtained by the gamma counter.

Fischer rats (9 weeks of age) were placed in a stereotaxic apparatus as described above. C6 glioma cells (2 × 105 cells/10 μl of culture media/rat) or vehicle (10 μl of culture media/rat) were injected at a rate of 0.7 μl/min into the left hippocampus of the rats (−4.7 mm posterior to bregma, −3.9 mm lateral to the midline suture, and −6.2 mm from the dura) via a microdialysis probe without a dialyzing membrane (four rats per group). Fourteen days after injection, 65ZnCl2 [20 μCi/0.3 ml of 0.1 m acetate buffer (pH 4.0)/300 g of body weight] or 14C-FDG (15 μCi/0.3 ml of saline/300 g of body weight) were injected into the tail vein of the rats. The rats were killed under deep diethyl ether anesthesia 1 h after injection of 65ZnCl2 or 14C-FDG. The brains excised from the rats were treated as described above.

Brain tumors were checked by carefully examining the slices and/or by stereomicroscopic observation of the slices (Olympus SZH10; Olympus Optical Co. Ltd., Tokyo, Japan) at the time of exposure to the imaging plates.

65Zn Distribution in Rats s.c. Implanted with Tumor Cells.

One h after i.v. injection of 65ZnCl2, 65Zn was concentrated in the tumor. 65Zn uptake in the tumor was higher than in the brain tissue (Fig. 1). 65Zn uptake in the tumor, however, was lower than in the liver. 65Zn uptake in the liver (in which zinc-metallothionein preferentially increases with the growth of tumors) of AH7974F-bearing rats was higher than in control rats, as reported previously (25, 26).

When the 65Zn concentration in the tumor was quantitatively compared with that in the brain and the blood, the 65Zn concentration in the AH7974F tumor was approximately three times higher than in the brain tissue and was approximately twice that in the blood (Table 1). In the C6 glioma-bearing rats, the 65Zn concentration in the C6 glioma was also relatively high. The tumor:brain and tumor:blood ratios were approximately 6 and 2, respectively (Table 1).

65Zn Distribution in the Brain of Rats Intracerebrally Implanted with Tumor Cells.

Brain autoradiography of normal rats demonstrated that 65Zn is concentrated in the choroid plexus 1 h after i.v. injection of 65ZnCl2 and that 65Zn concentration in the brain parenchyma is increased with a decrease in choroidal 65Zn (23). The maximum uptake of 65Zn in the brain parenchyma occurs ∼6 days after the injection (24). To image brain tumors with radioactive zinc, brain autoradiography with 65Zn was performed using rats intracerebrally implanted with AH7974F or C6 glioma cells. After implantation of AH7974F cells into the periaqueductual gray, 65Zn was highly concentrated in the tumor 1 h after injection of 65ZnCl2, whereas 65Zn concentration in other brain regions was remarkably low (Fig. 2,A). When the 65Zn concentration in the brains was quantitatively determined using a Bio-imaging analyzer, 65Zn uptake in the tumor was ∼10 times higher than in other brain regions and was approximately twice that in the choroid plexus (Fig. 3). 65Zn concentration in the brains of AH7974F tumor-bearing rats compared with control rats was significantly higher in the cerebral cortex, hippocampus, thalamus, hypothalamic nuclei, substantia nigra, and cerebellar lobules.

Rats intrahippocampally implanted with C6 glioma cells are used as a primary brain tumor model. One hour after injection of 65ZnCl2, 65Zn was highly concentrated in the tumor (Fig. 2,B). 65Zn uptake in the tumor was ∼10 times higher than in other brain regions and was ∼3 times higher than in the choroid plexus (Fig. 4). There was no significant difference in 65Zn concentration in the brain between C6 glioma-bearing and control rats, except in the tumor.

14C-FDG Distribution in the Brain of Rats Intracerebrally Implanted with C6 Glioma Cells.

[18F]FDG has been clinically used for diagnostic nuclear medicine of brain tumors. To evaluate tumor imaging with radioactive zinc, 14C-FDG imaging of brain tumors was also performed in rats intrahippocampally implanted with C6 glioma cells. One h after injection of 14C-FDG, 14C-FDG was concentrated in the tumor; 14C-FDG concentration in other brain regions was also relatively high (Fig. 2,C). As shown in Fig. 5, 14C-FDG uptake in the tumor was higher than in the hippocampus and was ∼1.5 times higher than in the contralateral region. There was no significant difference in 14C-FDG uptake between tumor and other brain regions, however, except in the hypothalamic nuclei.

Zinc serves as an endogenous neuromodulator in the brain (27). Zinc homeostasis in the brain is closely related to brain functions such as learning and memory and also to neurological disorders, such as epilepsy (28, 29). It is estimated that the turnover of functioning zinc in the brain, however, is much slower than in peripheral tissues, such as liver (27). Thus, there is a possibility that the movement of zinc related to proliferation and/or functions in malignant cells can be positively imaged with radioactive zinc in the brain. The whole-body autoradiography of AH7974F tumor-bearing rats demonstrated that 65Zn uptake in the tumor is higher than in the brain tissue 1 h after i.v. injection of 65ZnCl2, whereas 65Zn uptake in the tumor was lower than in the liver. The liver is an important organ for zinc metabolism in the body (30). The turnover of functioning zinc in the liver may be faster than in the tumor. When 65Zn uptake in the hepatoma and glioma, which were s.c. implanted into the inguinal region, was quantitatively compared to that in the brain, 65Zn uptake in both tumors was several times higher than in the brain. The present findings suggest that brain tumors can be positively imaged with radioactive zinc in the brain tissue.

Various nutrients are supplied to the brain parenchyma across the blood-brain and the blood-cerebrospinal fluid barriers. Glucose is a critical nutrient as the primary energy source for the brain. Although zinc is also a critical nutrient for brain functions, the transport of zinc, unlike glucose, is tightly restricted by the brain barrier systems (27). Angiogenesis is characteristic of tumors, including brain tumors, for acquisition of nutrients. The blood-brain barrier does not usually exist in brain tumors (31). Therefore, when brain tumors are positively imaged with radioactive zinc in the brain, it is expected that information relating to the viability of tumor cells will be obtained from the zinc image.

After implantation of AH7974F cells into the periaqueductal gray of rats, 65Zn uptake in the tumor was ∼10 times higher than in other brain regions 1 h after i.v. injection of 65ZnCl2. After implantation of C6 glioma cells into the hippocampus of rats, 65Zn uptake in the tumor was also much higher than in other brain regions. To compare the potential of 65Zn with that of [18F]FDG for the imaging of brain tumors, 14C-FDG imaging of the C6 glioma was performed in the same manner. Because a considerable amount of 14C-FDG was taken up in the brain, 14C-FDG uptake in the tumor was ∼1.5 times higher than in the contralateral region. The present findings demonstrate that 65Zn uptake may be more specific for brain tumors than is 14C-FDG uptake, suggesting the potential for 69mZn, a short-half-life γ emitter (t1/2, 13.76 h; energy, 439 keV), in the diagnosis of brain tumors by SPECT. It is likely that the information obtained by 69mZn SPECT will be different from that obtained by [18F]FDG PET.

201Tl is currently used for the diagnosis of brain tumors using SPECT, although it is highly concentrated in inflammatory regions in the brain (32). Because the ionic radius of thallium is close to that of potassium, thallium can mimic the movement of potassium. The disruption of the blood-brain barrier is important for 201Tl uptake in brain tumors. 201Tl transported into the brain extracellular fluid is taken up by tumor cells in proportion to the activity of the Na+-K+ pump, which somewhat reflects the metabolic activity of the tumors (1, 33). 99mTc and 67Ga, in addition to 201Tl, are used for brain tumor detection by SPECT. Because these elements are unnecessary for cell functions, however, the movement of these elements does not always reflect physiological response. On the other hand, 65Zn is concentrated in viable regions in peripheral tumor tissues (34). The net zinc uptake in C6 glioma cells occurs only above certain thresholds in time and concentration in vitro, which suggests that excessive zinc is not taken up in C6 glioma cells under physiological conditions (35). Therefore, when radioactive zinc is administered to the patients, it is likely that radioactive zinc transported into brain extracellular space is actively taken up in tumor cells and is used for the functions of the proliferating cells.

In conclusion, the present study demonstrates the potential for brain tumor imaging with 69mZn. Further investigation on prediction of the histological grade of brain tumors, prediction of prognosis, and evaluation of response to treatment is required to determine the extent of its usefulness.

Fig. 1.

65Zn imaging of AH7974F tumor-bearing rats. AH7974F cells were s.c. injected into rats. Ten days after implantation, 65ZnCl2 was i.v. injected into control and AH7974F tumor-bearing rats (n = 2). Autoradiography was performed 1 h after injection of 65ZnCl2. The experiment was performed twice, and the autoradiograms obtained were almost identical.

Fig. 1.

65Zn imaging of AH7974F tumor-bearing rats. AH7974F cells were s.c. injected into rats. Ten days after implantation, 65ZnCl2 was i.v. injected into control and AH7974F tumor-bearing rats (n = 2). Autoradiography was performed 1 h after injection of 65ZnCl2. The experiment was performed twice, and the autoradiograms obtained were almost identical.

Close modal
Fig. 2.

Brain tumor imaging. 65ZnCl2 was i.v. injected into rats 14 d after injection of vehicle (control) or AH7974F cells into the periaqueductal gray (A; n = 4). 65ZnCl2 was i.v. injected into rats 14 d after injection of vehicle or C6 glioma cells into the hippocampus (B; n = 4). 14C-FDG was i.v. injected into rats 14 d after injection of C6 glioma cells into the hippocampus (C; n = 4). Autoradiography was performed on selected coronal slices 1 h after injection of 65ZnCl2 or 14C-FDG. Each experiment was performed four times, and the autoradiograms obtained were almost identical. The schemes (left side) show maps of the rat brain. LV, lateral ventricle; 3V, third ventricle; Aq, aqueduct; HIP, hippocampus.

Fig. 2.

Brain tumor imaging. 65ZnCl2 was i.v. injected into rats 14 d after injection of vehicle (control) or AH7974F cells into the periaqueductal gray (A; n = 4). 65ZnCl2 was i.v. injected into rats 14 d after injection of vehicle or C6 glioma cells into the hippocampus (B; n = 4). 14C-FDG was i.v. injected into rats 14 d after injection of C6 glioma cells into the hippocampus (C; n = 4). Autoradiography was performed on selected coronal slices 1 h after injection of 65ZnCl2 or 14C-FDG. Each experiment was performed four times, and the autoradiograms obtained were almost identical. The schemes (left side) show maps of the rat brain. LV, lateral ventricle; 3V, third ventricle; Aq, aqueduct; HIP, hippocampus.

Close modal
Fig. 3.

65Zn distribution in the brain of AH7974F tumor-bearing rats. The radioactivity of each area in the autoradiograms from four control and four AH7974F-bearing rats obtained in Fig. 2 A was measured using a Bio-imaging analyzer. Each bar and line, mean ± SD (n = 4). Asterisks, significant difference (∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001; t test) from control (vehicle). Note that the 65Zn concentration in the tumor was significantly (P < 0.05; t test) higher than in any other brain region in AH7974F tumor-bearing rats.

Fig. 3.

65Zn distribution in the brain of AH7974F tumor-bearing rats. The radioactivity of each area in the autoradiograms from four control and four AH7974F-bearing rats obtained in Fig. 2 A was measured using a Bio-imaging analyzer. Each bar and line, mean ± SD (n = 4). Asterisks, significant difference (∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001; t test) from control (vehicle). Note that the 65Zn concentration in the tumor was significantly (P < 0.05; t test) higher than in any other brain region in AH7974F tumor-bearing rats.

Close modal
Fig. 4.

65Zn distribution in the brain of C6 glioma-bearing rats. The radioactivity of each area in the autoradiograms from four control and four C6 glioma-bearing rats obtained in Fig. 2 B was measured using a Bio-imaging analyzer. The C6 glioma had spread considerably in the brain. The 65Zn radioactivity of tumor areas in the autoradiograms from each rat was averaged. Each bar and line, mean ± SD (n = 4). The 65Zn concentration in the tumor was significantly (P < 0.05; t test) higher than in any other brain region in C6 glioma-bearing rats.

Fig. 4.

65Zn distribution in the brain of C6 glioma-bearing rats. The radioactivity of each area in the autoradiograms from four control and four C6 glioma-bearing rats obtained in Fig. 2 B was measured using a Bio-imaging analyzer. The C6 glioma had spread considerably in the brain. The 65Zn radioactivity of tumor areas in the autoradiograms from each rat was averaged. Each bar and line, mean ± SD (n = 4). The 65Zn concentration in the tumor was significantly (P < 0.05; t test) higher than in any other brain region in C6 glioma-bearing rats.

Close modal
Fig. 5.

14C-FDG distribution in the brains of C6 glioma-bearing rats. The radioactivity of each area in the autoradiograms from four C6 glioma-bearing rats obtained in Fig. 2,C was measured using a Bio-imaging analyzer. 65Zn concentration in the tumor was measured as described in Fig. 4. Each bar and line, mean ± SD (n = 4). ∗, significant difference (P < 0.05; t test) from tumor.

Fig. 5.

14C-FDG distribution in the brains of C6 glioma-bearing rats. The radioactivity of each area in the autoradiograms from four C6 glioma-bearing rats obtained in Fig. 2,C was measured using a Bio-imaging analyzer. 65Zn concentration in the tumor was measured as described in Fig. 4. Each bar and line, mean ± SD (n = 4). ∗, significant difference (P < 0.05; t test) from tumor.

Close modal

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

2

The abbreviations used are: CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; 14C-FDG, 2-fluoro-2-deoxy-[U-14C]glucose; PSL, photo-stimulated luminescence; SPECT, single-photon emission CT.

Table 1

65Zn concentration and tumor:tissue ratios

65Zn distribution in rats s.c. implanted with AH7974F or C6 glioma cells was determined 1 h after i.v. injection (n = 4).
Tumor % dose/g wet weight   Ratio  
 Tumor Brain Blood Tumor:Brain Tumor:Blood 
AH7974F 0.25 ± 0.08 0.08 ± 0.01 0.15 ± 0.05 3.1 1.7 
C6 glioma 0.75 ± 0.18 0.12 ± 0.02 0.46 ± 0.07 6.3 1.6 
65Zn distribution in rats s.c. implanted with AH7974F or C6 glioma cells was determined 1 h after i.v. injection (n = 4).
Tumor % dose/g wet weight   Ratio  
 Tumor Brain Blood Tumor:Brain Tumor:Blood 
AH7974F 0.25 ± 0.08 0.08 ± 0.01 0.15 ± 0.05 3.1 1.7 
C6 glioma 0.75 ± 0.18 0.12 ± 0.02 0.46 ± 0.07 6.3 1.6 
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