Jun Itoh

The accumulation of11C-methionine in cerebral glioma patients studied with PET

SummaryFourteen patients with cerebral gliomas were studied with positron emission tomography (PET) using L-[methyl-11C]methionine (11C-MET). Positive images of tumour were obtained in all cases regardless of histological grades. The analysis of differential absorption ratio (DAR) showed the higher accumulation of11C-MET in high grade gliomas than in low grade gliomas. PET study with11C-MET will be of great value not only in delineating the location of gliomas, but also in making a qualitative diagnosis from the view point of the biological properties of gliomas.

Clinical application of18F-FUdR in glioma patients — PET study of nucleic acid metabolism

SummaryPositron emission tomography was used to investigate the metabolism of nucleic acids by18F-fluoro-2′-deoxyuridine (18F-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 ± 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 ± 0.042 (p < 0.01). This PET-18F-FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.

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.

Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors.

Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified.

Ganglioside, Disialosyl Globopentaosylceramide (DSGb5), Enhances the Migration of Renal Cell Carcinoma Cells

About one third of renal cell carcinoma (RCC) patients exhibit metastasis upon initial presentation. However, the molecular basis for RCC metastasis is not fully understood. A ganglioside, disialosyl globopentaosylceramide (DSGb5), was originally isolated from RCC tissue extracts, and its expression is correlated with RCC metastatic potential. DSGb5 is synthesized by GalNAc α2,6-sialyltransferase VI (ST6GalNAcVI) and is expressed on the surface of RCC cells. Importantly, DSGb5 binds to sialic acid-binding Ig-like lectin-7 (Siglec-7) expressed on natural killer (NK) cells, thereby inhibiting NK-cell cytotoxicity. However, the role of DSGb5 in RCC progression remains obscure. To address this issue, we used ACHN cells derived from malignant pleural effusion of a patient with metastatic RCC. Using the limiting dilution method, we isolated three independent clones with different DSGb5 expression levels. Comparison of these clones indicated that the cloned cells with high DSGb5 expression levels exhibited greater migration potential, compared to the clone with low DSGb5 expression levels. In contrast, DSGb5 expression levels exerted no significant effect on cell proliferation. We then established the ACHN-derived cell lines that stably expressed siRNA against ST6GalNAcVI mRNA or control siRNA. Importantly, the ST6GalNAcVI-knockdown cells expressed low levels of DSGb5. We thus demonstrated the significantly decreased migration potential of the ST6GalNAcVI-knockdown cells with low DSGb5 expression levels, compared to the control siRNA-transfected cells expressing high DSGb5 levels, but no significant difference in the cell proliferation. Thus, DSGb5 expression may ensure the migration of RCC cells. We propose that DSGb5 expressed on RCC cells may determine their metastatic capability.

Docetaxel, cisplatin and 5‐fluorouracil chemotherapy with concurrent radiation for unresectable advanced urethral carcinoma

The present case report describes two cases of unresectable advanced primary urethral carcinoma. Case 1 was a 61‐year‐old man with squamous cell carcinoma of the urethra that directly invaded into the perineal skin. Case 2 was a 64‐year‐old woman with adenocarcinoma, and solitary lung and lymph node metastases. Both patients received docetaxel/cisplatin/5‐fluorouracil chemotherapy with concurrent radiation. The docetaxel/cisplatin/5‐fluorouracil chemotherapy regimen consisted of docetaxel (75 mg/m2) on day 2, cisplatin (100 mg/m2) on day 2 and 5‐fluorouracil (1000 mg/m2) on days 1 to 5 and was repeated every 4 weeks. Complete response was achieved after two cycles of chemotherapy combined with radiation in case 1. In case 2, complete response was achieved locally after six cycles of chemotherapy combined with radiation, but the solitary lung lesion remained viable. We experienced two cases with advanced urethral carcinoma for whom docetaxel/cisplatin/5‐fluorouracil chemotherapy chemotherapy with radiation was effective.

In vivo assessment of 6-deoxy-6-[18F]fluoro-d-galactose as a PET tracer for studying galactose metabolism

The potential of 6-deoxy-6-[18F]fluoro-D-galactose (6-[18F]FdGal) as an in vivo tracer for studying galactose metabolism in tumors and liver was investigated. High uptake and rapid clearance of the radioactivity were observed in many organs of mice after i.v. injection of the tracer. D-Galactose loading did not affect liver uptake. Three experimental tumors showed a slightly higher uptake than other tissues, and rat brain tumor was clearly visualized by autoradiography. However, the radioactivity in tumors decreased rapidly. In the liver, a significant amount of the tracer was found in a galactonate form, while this oxidation was a minor metabolic pathway in the tumors. In both tumor and liver tissues, small amounts of the tracer were incorporated into macromolecular glycoconjugate via phosphate and uridylate forms as intermediate precursors. These results indicate that 6-[18F]FdGal is not suitable for studying galactose metabolism in vivo because of the low affinity of the tracer for the metabolism.