Norio Takahashi

Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells

To reveal the metabolic fate of acetate in neoplasms that may characterize the accumulation patterns of [1-(11)C]acetate in tumors depicted by positron emission tomography. Four tumor cell lines (LS174T, RPMI2650, A2780, and A375) and fibroblasts in growing and resting states were used. In uptake experiments, cells were incubated with[1-(14)C]acetate for 40 min. [(14)C]CO(2) was measured in the tight-air chamber, and the metabolites in cells were identified by thin layer chromatography and paper chromatography. The glucose metabolic rate of each cell line was measured with [2,6-(3)H]2-deoxy-glucose (DG), and the growth activity of each cell line was estimated by measuring the incorporation of [(3)H]methyl thymidine into DNA. Compared with resting fibroblasts, all four tumor cell lines showed higher accumulation of (14)C activity from [1-(14)C]acetate. These tumor-to-normal ratios of [1-(14)C]acetate were larger than those of DG. Tumor cells incorporated (14)C activity into the lipid-soluble fraction, mostly of phosphatidylcholine and neutral lipids, more prominently than did fibroblasts. The lipid-soluble fraction of (14)C accumulation in cells showed a positive correlation with growth activity, whereas the water-soluble and CO(2) fractions did not. These findings suggest that the high tumor-to-normal ratio of [1-(14)C]acetate is mainly due to the enhanced lipid synthesis, which reflects the high growth activity of neoplasms. This in vitro study suggests that [1-(11)C]acetate is appropriate for estimating the growth activity of tumor cells.

Prognostic value of an increased in flourine-18 deoxyglucose uptake in patients with myocardial infarction: Comparision with stress thallium imaging

OBJECTIVES This study was undertaken to evaluate the prognostic value of an increase in fluorine (F)-18 deoxyglucose uptake compared with clinical, angiographic and stress thallium findings in patients with myocardial infarction. BACKGROUND Positron emission tomography (PET) imaging using F-18 deoxyglucose has been applied to assess tissue viability in patients with coronary artery disease. We hypothesized that patients with a myocardial segment with augmented F-18 deoxyglucose uptake are at high risk for a future cardiac event. METHODS One hundred fifty-eight consecutive patients with myocardial infarction referred for F-18 deoxyglucose PET and stress thallium scans were studied. Follow-up was obtained in 84 patients at a mean interval of 23 months to investigate prognostic implications of radionuclide studies. RESULTS Seventeen patients had a cardiac event during the follow-up interval. Univariate analysis showed that an increase in F-18 deoxyglucose uptake was the best predictor of a future cardiac event (p = 0.0006), followed by the number of stenosed vessels (p = 0.008). In the multivariate analysis, when an increase in F-18 deoxyglucose uptake was entered into the model, only angiographic variables had an independent prognostic value, whereas no other radionuclide variables showed significant prognostic value. Among patients who did not show redistribution, a future cardiac event was observed more often in patients with than in those without an increase in F-18 deoxyglucose uptake (p < 0.05). CONCLUSIONS Thus, an increase in F-18 deoxyglucose uptake seemed to be the best predictor of a future cardiac event among all clinical, angiographic and radionuclide variables in this study of stable patients with myocardial infarction. Even when a stress thallium-201 scan does not show redistribution, those patients who have an increase in F-18 deoxyglucose uptake in a PET study may be at risk for a future cardiac event, and these patients may need aggressive treatment to prevent a future cardiac event.

Evaluation of62Cu labeled diacetyl-bis(N 4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer

Abstract62Cu labeled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator-produced, positron-emitting tracer for hypoxic tissue imaging. From basic studies, the retention mechanism of62Cu-ATSM is considered to be closely related to cytosolic/microsomal bioreduction, a possible system for hypoxic bioreductive drug activation. In order to evaluate the characteristics of62Cu-ATSM, PET studies were performed in 4 normal subjects and 6 patients with lung cancer.62Cu-ATSM cleared rapidly from the blood with little lung uptake (0.43±0.09, uptake ratio; divided by the arterial input function) in normal subjects. Intense tumor uptake of62Cu-ATSM was observed in all patients with lung cancer (3.00±1.50). A negative correlation was observed between blood flow and flow-normalized62Cu-ATSM uptake in three of four patients. In contrast,62Cu-ATSM uptake was not related to that of18F-fluorodeoxyglucose. The negative correlation between blood flow and flow normalized62Cu-ATSM uptake suggests an enhancement of retention of62Cu-ATSM by low flow.62Cu-ATSM is a promising PET tracer for tumor imaging, which might bring new information for chemotherapeutic treatment as well as radiotherapy of hypoxic tumors.

Ester linkages between lignin and glucuronoxylan in a lignin-carbohydrate complex from beech (Fagus crenata) wood

SummaryA water-soluble lignin-carbohydrate complex (LCC) isolated from beech (Fagus crenata) MWL was investigated. Results from gelfiltration chromatography and the infrared spectrum of the LCC treated with alkali under mild conditions indicated that the LCC contained alkali-labile bonds. Decrease of uronic acid content and the detection of 4-O-methylglucose in the sodium borohydride-reduced LCC suggested the presence of an ester linkage between lignin and glucuronic acid in the glucuronoxylan. Conductometric titration also indicated the existence of glucuronic acid ester linked to lignin. From these results, it is concluded that the LCC contained an ester linkage between lignin and glucuronoxylan and that about one-third of the glucuronic acid present in the LCC was involved in this ester linkage.

Copper-62 ATSM as a hypoxic tissue tracer in myocardial ischemia

Copper-62 labeled diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator produced positron-emitting tracer for hypoxic tissue imaging. To clarify the usefulness of62Cu-ATSM for myocardial ischemia,62Cu-ATSM PET was performed in 7 patients with coronary artery disease. Increased myocardial uptake of62Cu-ATSM was observed (myocardium/blood ratio: 3.09) in one patient with unstable angina, who had increased18F-fluorodeoxyglucose (18F-FDG) uptake under the fasting condition. The other 6 patients, who were clinically stable, did not have increased62Cu-ATSM uptake, although abnormal18F-FDG uptake was seen in 4 patients. This preliminary study suggests that62Cu-ATSM is a promising PET tracer for hypoxic imaging in acute ischemia.

CCl2(Ã 1B1) radical formation in VUV photolyses of CCl4 and CBrCl3

In vacuum ultraviolet photolyses of CCl4 and CBrCl3 a diffuse emission band was observed in the region of 410–750 nm by Ar i resonance and H Lyman‐α line irradiation. The band was attributed to a CCl2(A 1B1 → X 1A1) transition from the measurements of the appearance energies of the emitters produced from photodissociative excitation of both CCl4 and CBrCl3 using synchrotron radiation. The fluorescence decay of the CCl2(A → X) transition showed a superposition of two lifetime components of 2.17±0.26 and 4.0±0.12 μs at pressures from 10 to 140 mTorr. The pressure dependence of the amplitudes for the two lifetimes suggests the occurrence of collision‐induced intersystem crossing between 1B1 and 3B1 states of CCl2 radicals. The absorption cross section of CBrCl3 was measured for the first time in the 106–200 nm wavelength region and tentative assignments of Rydberg transitions are presented.

Myocardial uptake of 99mTc-tetrofosmin, sestamibi, and 201Tl in a model of acute coronary reperfusion

BACKGROUND To investigate whether tetrofosmin uptake is affected by myocardial viability as has been noted for 201Tl and sestamibi, we analyzed the initial and delayed distribution patterns of tetrofosmin in a rat coronary artery occlusion-reperfusion model. METHODS AND RESULTS Animals were intubated and ventilated, and their arterial pressures were monitored. A left thoracotomy was performed. After 1-hour occlusion and 1-hour reperfusion of a major branch of the circumflex artery, 201Tl and either tetrofosmin or sestamibi were injected intravenously. Radiolabeled microspheres were used to document the area at risk and reperfusion. Five minutes or 1 hour after administration of the diffusible tracers, the animals were killed. Tracer distribution was determined by use of segmental tissue analysis, and tissue viability was determined by use of histochemical staining. Both the initial and delayed retention of tetrofosmin were sensitive to myocardial viability, as shown by significantly lower uptake (30 +/- 14%) and retention (24 +/- 12%) of tetrofosmin in the nonviable segments compared with the viable segments. In addition, the initial myocardial distribution of tetrofosmin was similar to that noted for 201Tl, but after 1 hour of tracer circulation, the tetrofosmin tissue distribution appeared unchanged compared with the initial regional blood flow distribution. This is in direct contrast to our present observations of significant 201Tl redistribution and some changes in sestamibi distribution as well. CONCLUSIONS The clinical implication of these observations suggests that initial and delayed imaging after tetrofosmin administration would reflect both the initial regional blood flow pattern and myocardial viability.

Oxidative metabolism in the myocardium in normal subjects during dobutamine infusion.

To assess the biventricular response of the clearance rate of carbon-11 acetate as an index of myocardial oxidative metabolism to increase in work-load, dynamic positron emission tomography was performed at rest and during dobutamine infusion in 14 normal subjects. The clearance rate constant (Kmono) of the left ventricular (LV) myocardium increased during dobutamine infusion (0.112±0.020 min−1 vs 0.065±0.015 min−1 at rest) (P<0.001) in proportion to the increase in the pressure-rate product. Kmono in the right ventricular (RV) myocardium also increased (0.080±0.018 min−1 vs 0.034±0.013 min−1 at rest) (P<0.001), with an excellent correlation with the LV Kmono (r=0.920). The fact that the increase in RV Kmono during dobutamine infusion was greater (158%±81%) than that in LV Kmono (79%±39%) (P < 0.005) indicates a greater increase in oxidative metabolism in the RV in response to inotropic stimulation in normal subjects.

Combined assessment of regional perfusion and wall motion in patients with coronary artery disease with technetium 99m tetrofosmin

BackgroundTechnetium 99m tetrofosmin is a new99mTc-labeled myocardial perfusion agent that can be labeled easily and provides excellent myocardial perfusion images. In addition, bolus administration of the tracer allows first-pass radionuclide ventriculography.Methods and ResultsThis study examined the diagnostic value of combined assessment of regional perfusion by tetrofosmin tomography and wall motion by first-pass radionuclide ventriculography both at rest and during stress in 24 patients suspected of having coronary artery disease. All patients underwent stress-rest tetrofosmin tomography, stress-delayed thallium 201 tomography, and coronary angiography. Stress tetrofosmin tomography showed abnormal perfusion in all 23 patients with angiographic evidence of coronary artery disease, whereas stress201Tl tomography showed abnormal perfusion in 22 of the 23 patients. For detection of significant (≥50% diameter stenosis) stenotic coronary arteries, the two perfusion studies showed similar sensitivities (62% with201Tl and 69% with tetrofosmin) and specificities (88% and 100%, respectively). When analysis of regional wall motion was combined with perfusion study, a slightly higher sensitivity was obtained (77%), with similar specificity. The regional wall motion score was concordant with the regional perfusion score in only 42% of the segments at rest and 50% during exercise.ConclusionsThese results suggest that stress tetrofosmin perfusion tomography and stress201Tl tomography provided similar diagnostic accuracy for detection of coronary artery disease. The combined assessment of perfusion and function that is feasible with tetrofosmin may enhance diagnostic accuracy in patients with coronary artery disease.

Assessment of myocardial fatty acid metabolism with positron emission tomography at rest and during dobutamine infusion in patients with coronary artery disease

The myocardial clearance rate of C-11 palmitate as an index of fatty acid oxidation was assessed by means of positron emission tomography (PET) at rest and during dobutamine infusion in seven normal subjects and 10 patients with coronary artery disease. In the normal subjects the clearance half time was homogeneous in the left ventricle at rest and uniformly shortened during dobutamine infusion. In the myocardium at risk, clearance half time tends to be longer in the segments with an abnormal Q wave on ECG, exhibiting regional wall motion abnormality, and supplied by severely stenosed coronary arteries, particularly during dobutamine infusion. These data indicate that fatty acid oxidation may be decreased in infarcted myocardium and associated with regional asynergy. Such an abnormality was most striking in those with severe coronary stenosis during dobutamine infusion. We conclude that PET with the use of C-11 palmitate at rest and during dobutamine is a useful means of identifying impaired fatty acid oxidation and decreased metabolic reserve in patients with coronary artery disease.