Masao Tada

Clinical assessment of therapeutic effects on cancer using 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography: preliminary study of lung cancer.

Using positron emission tomography, we studied the tumor uptake of 18F-2-fluoro-2-deoxy-D-glucose (18FDG) in five lung cancer patients before and after anti-cancer therapy (radiotherapy and/or chemotherapy). The tumor uptake of 18FDG was classified as positive and negative; the former, by increasing the uptake of 18FDG with time, and the latter, by decreasing or the constant uptake of 18FDG. Before therapy, all cases tested positive. After therapy, three cases were negative and two cases remained positive. All negative cases corresponded to complete second 18FDG study. Our findings in the 18FDG study correlate with the clinical results. 18FDG is a promising method for assessing therapeutic effects on cancer clinically.

Evaluation of the treatment response of lung cancer with positron emission tomography and l-[methyl-11C]methionine: a preliminary study

We carried out a study to evaluate treatment response and residual mass in lung cancer with positron emission tomography (PET), using l-[methyl-11C]methionine (MET). MET tumour uptake and tumour volume measured by computed tomography (CT) before and within 2 weeks after radiotherapy or chemoradiotherapy were compared in 43 studies of 21 patients. Ten patients with local control (no recurrence) of tumour showed a larger decrease in MET uptake (65.2%±12.2%) than in tumour volume (50.8%±9.6%, P<0.01). Five patients with early recurrence (from 1 to 4 months) showed smaller decreases in both MET uptake (22.2%±13.5%) and tumour volume (28.6%±20.0%) than those in the no-recurrence group (P<0.01). Four patients with late recurrence (after 11 months or more) showed a similar decrease to the no-recurrence group in MET uptake (72.8%±14.8%) but little change in tumour volume (18.5%±19.0%), the latter result corresponding to that in the early-recurrence group. Using tumour volume only, the no-recurrence group was differentiated from both the early- and the late-recurrence group (P < 0.01), but the early-recurrence group was not differentiated from the late-recurrence group. Using the MET uptake data, the early-recurrence group was clearly distinguished from the late-recurrence group (P<0.01), but the late-recurrence group was indistinguishable from the no-recurrence group. CT was useful in distinguishing the no-recurrence group from the groups in which there was ultimate recurrence, whether early or late. When a residual mass is seen on CT, PET seems to be helpful in evaluating tumour viability.

Differential diagnosis of AH109A tumor and inflammation by radioscintigraphy with L-[methyl-11C]methionine.

For the evaluation of tumor imaging with l‐[methyl‐11C]methionine (11C‐Met), a basic study on the differentiation of tumor from inflammation with 11C‐Met and a comparison of the diagnostic value of the image with that obtained using 67Ga citrate, a conventional scintigraphic agent, are important. 11C‐Met accumulations into inflammatory lesions, AH109A tumor and normal tissues of rats were examined by means of a tissue distribution study. Aseptic inflammatory lesions on the back of Donryu rats induced by croton oil and 1.5% carrageenan showed significantly lower accumulations of 11C‐Met than the AH109A tumor. Histologically, croton oil induced granulomatous inflammation and carrageenan, acute exudative inflammation. Whole‐body antoradiography with l4C‐Met, a substitute for 11C‐Met, was negative in the carrageenan lesion and showed a slightly increased activity at the periphery of the croton oil lesion, in contrast with the high tumor activity. Whole‐body autoradiogra‐phy with 67Ga citrate was performed to compare the imaging ability with that of 14C‐Met; it showed high activities in the tumor, bone, and intestine, and a broad increased activity at the periphery of the croton oil lesion, but was negative in the carrageenan lesion. 11C‐Met accumulations in the inflammations were very low and clinical application with positron emission tomography, should be useful for the differential diagnosis of tumor from inflammation.

2-deoxy-2-[18F]fluoro-d-galactose: A new tracer for the measurement of galactose metabolism in the liver by position emission tomography

We prepared 2-deoxy-2-[18F]fluoro-d-galactose as a potential radiopharmaceutical for liver imaging and for the assessement by position emission tomography of regional metabolic function of the liver. In biodistribution studies of rats, the liver uptake of the compound was very high, almost reaching a plateau (6.33% dose/g) at 30 min and remaining constant until 120 min. This high uptake was reduced by simultaneous administration of d-galactose, but d-glucose had no effect. The compound was much less concentrated in the liver that had been damaged by CCl4 treatment. Positron imaging of a rabbit liver showed a remarkable uptake of the compound with a high liver-to-blood ratio. The high concentration in the liver was also reduced by the administration of d-galactose. These data suggest that the compound was trapped in the liver by a metabolic process and could be used for the measurement by position emission tomography of galactose metabolism in the liver.

Effects of radiotherapy on the cellular uptake of carbon-14 labeledl-methionine in tumor tissue

In order to examine in vivo effects of irradiation on tumor uptake of L-[methyl-11C]methionine at a cellular level, the distribution of L-[methyl-14C]methionine (Met) in a rat AH109A tumor model was investigated using microautoradiography. Silver grain density of tumor cell layer decreased rapidly within the first day after 20 Gy of irradiation, and continued to fall during day 2. Grain density of granulation tissue was 25% of tumor cells and was unchanged after irradiation. Macrophages and necrotic tissue showed low grain density and a small post-irradiation decrease. One day after irradiation, tumor cell showed giant cell formation and decreased cell density per unit area. The number of grains was greater in giant tumor cells than in non-irradiated tumor cell. Rapid response of Met uptake by tumor cells without a significant uptake by granulation tissue and macrophages suggest that 11C-Met is a suitable tracer for monitoring tumor radiotherapy with positron emission tomography.

Actions of amino-β-carbolines on induction of sister-chromatid exchanges

Abstract Synthetic 3-aminoharman and 3-aminonorharman (amino-β-carbolines) caused slight but definite induction of sister-chromatid exchanges (SCEs) in human lymphoblastoid cells NL3 and Chinese hamster cells CHO-K1. These amino-β-carbolines are ranked between 2-amino-α-carboline and 2-amino-6-methyl-9a-aza-δ-carboline (Glu-P-2) and much lower than 3-amino-γ-carbolines (Trp-P-1 and 2) in inductive activity. 1-Amino-β-carboline, harman and norharman had very weak, if any, SCE-inducer activity. Norharman had a synergistic effect with aromatic amines such as Trp-P-2 and aniline on SCE induction, while 3-aminoharman suppressed SCE induction by more potent inducers such as Trp-P-2 and benzo[ a ]pyrene.

Column extraction method for rapid preparation of [11C]acetic and [11C]palmitic acids

Abstract A rapid method suitable for the routine preparation of [ 11 C]acetic and [ 11 C]palmitic acids is described. The reaction of [ 11 C]carbon dioxide with a Grignard reagent and purification by liquid-liquid extraction were carried out in a liquid layer supported by a commercially available kieselguhr, Extrelut R (Merck). [ 11 C]Carbon dioxide was efficiently trapped into a reagent solution kept by an Extrelut column and the free [ 11 C]fatty acid formed by quenching with diluted HCl was sequentially extracted by flowing an appropriate organic solvent from the reaction column into the solvent and then from the solvent into a short column of Extrelut for [ 11 C]acetic acid or silica gel for [ 11 C]palmitic acid. Thus, using this on-line method based on column extraction, [ 11 C]acetic acid was prepared in over 90% radiochemical yield and [ 11 C]palmitic acid in approx. 50% radiochemical yield, within 15 min, with the same system and procedure.

2-Deoxy-2-[18F]fluoro-d-galactose as an In Vivo tracer for imaging galactose metabolism in tumors with positron emission tomography

The feasibility of 2-deoxy-2-[18F]fluoro-D-galactose ([ 18F]FdGal) for imaging galactose metabolism in tumors with positron emission tomography (PET), was investigated using two hepatomas, Yoshida sarcoma, or glioma in rats, and mouse mammary carcinoma. In hepatoma-bearing rats the highest uptake of [18F]FdGal was observed in the liver followed by the kidney and tumor. The tumor uptake increased with time, and the high uptake ratios of tumor to organ were observed except for the liver and kidney. Tumor uptake was also measured in all tumors. As main metabolites in all tumors, [18F]FdGal 1-phosphate and UDP-[18F]FdGal were found by HPLC. Two hepatomas showed a slightly higher uptake and a larger percentage of UDP derivative than the other three tumors. By autoradiography the brain tumor was visualized clearly. These results indicate that [18F]FdGal has potential as a tracer for imaging galactose metabolism in tumors with PET.

Dose-responsive effect of radiotherapy on the tumor uptake of L-[methyl-11C]methionine; feasibility for monitoring recurrence of tumor

The L-[methyl-11C]methionine [( 11C]Met) uptake by rat AH109A tumor was decreased irradiation-dose dependently from the control to 5, 10 and 20 Gy. After 10 Gy irradiation, the [11C]Met uptake decreased earlier than the tumor volume reduction, and later, it significantly increased earlier than the recurrent growth. Double tracer autoradiography with [14C]Met and 4-[18F]fluoroantipyrine showed a decrease in the [14C]Met tumor uptake without change of blood flow after irradiation. The [11C]Met uptake representing amino acid metabolism is a sensitive indicator for monitoring radiotherapeutic effect on tumor.

Accumulation of 2-deoxy-2-[18F]fluoro-d-galactose in the liver by phosphate and uridylate trapping

To investigate the highest accumulation of 2-deoxy-2-[18F]fluoro-D-galactose ([18F]FdGal) in the liver, metabolic studies with [18F]FdGal were carried out in Wistar rats for 120 min after i.v. injection. As main metabolites 2-deoxy-2-[18F]fluoro-D-galactose 1-phosphate ([18F]FdGal-1-P) and UDP-2-deoxy-2-[18F]-fluoro-D-galactose (UDP-[18F]FdGal) were identified in the liver and other tissues. The [18F]FdGal was phosphorylated by galactokinase. The phosphorylation rate was very rapid in the liver, in which at 5 min after injection 81% of 18F was detected as [18F]FdGal-1-P. After this time the phosphate form decreased with time, which was explained by conversion of [18F]FdGal-1-P to UDP-[18F]FdGal by UDP-glucose: galactose-1-phosphate uridyltransferase. At 120 min after injection 77% of the 18F was measured in the UDP-[18F]FdGal. In the brain both reaction rates were slower than in the liver. Both phosphate and uridylate derivates were also observed as main metabolites in the heart, lung, spleen and small intestine. On the other hand, a small amount of [18F]FdGal-1-P was detected in the plasma, in which the percentage of phosphate increased gradually and was 6% at 120 min. These results show that the [18F]FdGal metabolism in tissue results in phosphate and uridylate trapping and that the [18F]FdGal has potential for measuring in vivo galactose metabolism with positron emission tomography.