Comparison of sestamibi, tetrofosmin, and Q12 retention in porcine myocardium.

UNLABELLED: Although there are several 99mTc perfusion tracers introduced for clinical use, there are no data available directly comparing these tracers with microsphere-determined flow. The aim of this study was to compare the myocardial retention of sestamibi, tetrofosmin, and Q12 in a porcine model. METHODS: We used a pig model with (n = 6) or without (n = 3) coronary occlusion. Each pig received a simultaneous injection of sestamibi and either tetrofosmin (group 1, n = 5) or Q12 (group 2, n = 4) labeled with either 99mTc or 95mTc (physical half-life, 61 d; photon energy, 204 keV) during pharmacologic vasodilation. Absolute myocardial retention of each tracer was calculated from the myocardial tracer activity and arterial input function. RESULTS: The plot of all three tracers versus flow achieved a plateau at a higher flow range. However, sestamibi showed a higher mean retention than either tetrofosmin (group 1, 0.27 +/- 0.11 vs. 0.16 +/- 0.06 mL/g/min, respectively; P < 0.01) or Q12 (group 2, 0.32 +/- 0.13 vs. 0.09 +/- 0.03 mL/g/min, respectively; P < 0.01). Furthermore, when a linear regression analysis was performed to assess the relationship between retention and microsphere-determined flow, sestamibi showed a greater increment in retention than did tetrofosmin or Q12. CONCLUSION: Although all of the tracers showed a nonlinear increase in retention as flow increased, sestamibi may display more favorable characteristics as a flow tracer in the porcine heart.

Fluorine-18-FDG PET and iodine-123-IMT SPECT in the evaluation of brain tumors.

UNLABELLED: The high glucose utilization of normal gray matter limits the detection of brain tumor tissue by PET using 18F-fluorodeoxyglucose (FDG). The aim of this study was to evaluate whether the examination of amino acid transport with the SPECT tracer 123l-alpha-methyl-L-tyrosine (IMT) allows better identification of tumor tissue than FDG-PET. METHODS: Nineteen patients (16 with gliomas, 3 with nontumorous lesions) were included in the study. Two independent observers classified PET and SPECT images as positive or negative for tumor tissue and defined the extent of tumor with regions of interest. Tracer uptake of FDG and IMT was quantified by calculating the tumor uptake relative to contralateral gray and white matter. RESULTS: SPECT studies were interpreted concordantly in 18 patients (kappa = 0.77) and all tumors were identified by both observers. PET studies were interpreted discordantly in 4 patients (kappa = 0.52) and only 10 tumors were identified by both observers, interobserver variability in definition of tumor extent was significantly lower in the IMT-SPECT than in the FDG-PET studies (p = 0.03). Mean tumor uptake relative to gray and white matter was 1.93 +/- 0.42 and 2.25 +/- 0.46 for IMT and 0.93 +/- 0.32 and 1.61 +/- 0.52 for FDG. All tumor uptake ratios were significantly (p < 0.01) higher for IMT than FDG, even when only glioblastomas were analyzed. No significant correlation was observed between the various uptake ratios of FDG and IMT. CONCLUSION: Despite the lower resolution and lower sensitivity of SPECT compared with PET, IMT-SPECT was clearly superior to FDG-PET in the detection and delineation of tumor tissue.

Radiation-induced transient cisplatin resistance in murine fibrosarcoma cells associated with elevated metallothionein content.

Cisplatin resistant mouse fibrosarcoma cells were isolated after fractionated irradiation in the absence of any drug treatment. Several sublines have been established; clone SSK-rad1 was used for further studies. These cells exhibit unchanged radiosensitivity and are compared to cisplatin resistant sublines, SSK-cis2, previously induced by low dose cisplatin exposure. Both resistant sublines are characterised by reduced CdCl2 sensitivity, indicating enhanced metallothionein content; loss of cisplatin resistance occurs after 10 to 25 generations and correlates with rising CdCl2 toxicity. Increase of MT is demonstrated directly by 109Cd binding to the MT containing region after FPLC. Both sublines differ in GSH level, which is increased only in SSK-rad1 cells, and in cellular platinum content, which is reduced in SSK-cis2 cells compared to the parental SSK cell line. These factors may contribute to cisplatin resistance but are not the main cause responsible for the transient nature of the drug resistance observed. Our results indicate that transient cisplatin resistance in SSK cells can be induced not only by the drug itself but also by gamma-irradiation and is based on the same mechanism of increased cellular MT content.

Transient cisplatin-resistant murine fibrosarcoma cell characterized by increased metallothionein content.

Cisplatin-resistant mouse fibrosarcoma cells, SSK-R, were isolated after short and low-dose drug treatment of the sensitive SSK cells in vitro. These SSK-R sublines exhibit up to sevenfold cisplatin resistance and are characterized mainly by an increased metallothionein content. Loss of drug resistance after about 140-180 cell divisions in drug-free medium coincides with loss of metallothionein content. The glutathione level is the same in the sensitive and resistant sublines; inhibition of glutathione synthesis by buthionine sulphoximine enhances the sensitivity in both cells lines by a factor of 2.7. The resistant sublines are not cross-resistant to radiation; a radiation exposure followed immediately by cisplatin treatment results in an additive effect. The cellular cisplatin content is slightly reduced in SSK-R2 cells and it remains at this level also upon loss of drug sensitivity.

[Organ specific deposition of 45Ca labelled calcium phosphate ceramic material]. / Zur organspezifischen Ablagerung von 45Ca-markierter Kalziumphosphatkeramik.

Research work using easily resorbable HA- und TCP-ceramics does not give any proof for pathologic deposition in different organs. Based on current information, there is no objection against the clinical use of HA-ceramics.

Curative radioimmunotherapy of human mammary carcinoma xenografts with iodine-131-labeled monoclonal antibodies.

The radioiodinated monoclonal antibody BW 495/36 showed an exceptionally high uptake and long residence time in human ductal mammary carcinoma xenografts in nude mice. There was a mean tumor uptake of 82%/g 24 hr p.i., decreasing with a biologic half-life of approximately 6 days, to 15%/g by Day 16. The tumor-to-blood ratio increased from 2.8 to 21.4 and the percentage of the whole-body retention recovered in the tumor from 47% to 80% during the same time interval. The therapeutic efficiency of two injections of 7.4 MBq 131I-BW 495/36 was evaluated by comparing the tumor size with that in mice injected with either the same amount of the unlabeled MoAb, the same radioactivity of an 131I-labeled nonspecific MoAb, or with saline only. The high tumor accumulation of 131I-BW 495/36 led to a total tumor dose of 77 Gy resulting in a mean reduction in tumor diameter of 50%, corresponding to a reduction in tumor volume of 88% within 42 days p.i. Unlabeled MoAb had no effect on tumor growth compared with controls, whereas 131I nonspecific antibody caused a slight inhibition of tumor growth. Histologic tumor sections showed large areas of necrosis and a pronounced vacuolation of the tumor cell cytoplasm between Days 7 and 30 p.i. By Day 42 all remaining tissue in the tumor was identified as mouse connective tissue.

Improved radioimmunoscintigraphy of human mammary carcinoma xenografts after injection of an anti-antibody.

The low tumor-to-background ratio obtained after administration of radiolabeled whole monoclonal antibodies (MAbs) is one of the major problems in immunoscintigraphy and -therapy. To reduce the blood pool label caused by the circulation of radiolabeled MAb we have investigated the advantage of injecting an anti-antibody after administration of a tumor-specific MAb in nude mice bearing human mammary carcinoma xenografts. The MAb MA 10-11 of rat origin, used in these studies, had shown a high affinity to human mammary carcinoma tissue on frozen sections and low cross-reactivity with various normal human tissues. 24 h after injection of 1.5 MBq 131I-labeled MAb containing 10 micrograms IgG2a one group of mice received an additional injection of 100 micrograms anti-rat antibody. Blood taken 2 min after the second antibody injection showed nearly the whole activity bound to antibody aggregates, that cleared very rapidly from the circulation and accumulated in liver and spleen. The transitory high liver activity decreased within several hours because of rapid deiodination of the antibody-complex in this organ. The release of radioactivity from the spleen, however, was found to be much slower. The rapid excretion of the radioactivity from the blood pool combined with a nearly constant tumor activity allowed early tumor detection with tumor-to-blood ratios of 250:1 at 48 h after anti-antibody injection compared to 1.1:1 obtained for the control animals. In addition the results may explain the reported reduction of imaging quality and high uptake of radioactivity in the spleen of patients having repeated injections of mouse MAbs due to complex formation after development of human anti-mouse antibodies.

Measurement of myocardial fatty acid metabolism: kinetics of iodine-123 heptadecanoic acid in normal dog hearts.

To define the potential of iodine-123 heptadecanoic acid (IHA) for the noninvasive assessment of myocardial fatty acid metabolism with gamma camera imaging, the influence of myocardial oxygen consumption (MVO2) and blood flow (MBF) on extraction and half-times of IHA were investigated in dogs. Following IHA injection into the left circumflex coronary artery, extraction fraction and half-times were derived from the peak and slope of the IHA time activity curve, which consisted of a vascular, early, and late phase. Single-pass extraction fraction of IHA averaged 0.53 +/- 0.11 s.d. at control and was not influenced by MVO2 and MBF. The half-time of the early phase (T = 9.3 min +/- 2.8 s.d. in controls) as well as the ratio between the size of the early and late phase increased with MVO2 (r = 0.82, r = 0.87, respectively). Thus, early phase intracellular turnover of IHA increased, yet clearance of 123I activity was slowed by augmented cardiac work. Preliminary data of HPLC and electrophoretic analysis of myocardial arterial and venous blood samples over time indicate that the early phase is characterized by a decreasing washout of IHA and a relative increase of radioiodine washout. The half-time of the late phase (T = 245 min +/- 156 s.d. at control) was not related to MVO2 and MBF. In conclusion, myocardial fatty acid metabolism cannot be measured from the half-time of the early phase but might be analyzed from the ratio between the size of the early and late phase when using IHA.

Determination of androgen receptors in human benign prostatic hypertrophy with two synthetic radiolabeled ligands.

Nuclear and cytosolic androgen receptor concentrations in tissues of human benign prostatic hypertrophy (BPH) were determined by use of methyltrienolone (R-1881) and 7 alpha,17 alpha-dimethyl-19-nortestosterone (DMNT) as radiolabeled ligands. Cytosolic R-1881-binding sites were 46.1 +/- 43 fmol/mg protein and nuclear R-1881-binding sites were 51.8 +/- 42 fmol/mg protein. DMNT-binding sites in cytosol were 44.3 +/- 38 fmol/mg protein and in nuclear extract 73.4 +/- 64 fmol/mg protein. No significant correlation was found between the number of R-1881- and DMNT-binding sites in either cytosol or nuclear extracts. Cytosolic or nuclear androgen receptor content was not significantly correlated with the percentage of epithelial or stromal cells as determined from the corresponding histological sections. In BPH tissue with marked cystic degeneration, very low androgen receptor levels were found.

Natural killer cells in patients with renal cell cancer.

Cytotoxic activity of natural killer (NK) cells in peripheral blood was studied in 60 patients with renal cell carcinoma (RCC) by means of a 51Cr release assay against K 562 cells, homologous and autologous RCC. All patients were tested prior to surgery and thereafter followed up for 1 year. Immunostimulating agents as interferon, levamisole, OMPI, and various bacterial extracts were tested for their boosting capacity on NK cells. Patients with localized tumor showed increased activity in comparison to age-matched controls, whereas NK cell activity and interferon-boosted activity in patients with advanced disease and tumor spread was decreased. Augmentation of NK activity could only be achieved by interferon, while application of levamisole, OMPI, and bacterial extracts resulted rather in suppression of cytotoxic activity.

Preparation and purification of omega-(p-123I-iodophenyl)-pentadecanoic acid.

A method for the preparation of 123I iodinated omega-phenyl-pentadecanoic acid (PPA) and a two-step separation of the o- and p-isomers is described. 98% pure p-iodophenyl-pentadecanoic acid is obtained within 3 h.

In vivo and in vitro studies with omega-[rho-123I-phenyl]-pentadecanoic acid in rats.

Biodistribution, plasma clearance and urinary excretion of omega-[p-123I-phenyl]-pentadecanoic acid were investigated in rats. The affinity of this radiopharmaceutical to red blood cells and to the plasma proteins was determined in vitro. Various radioactive metabolites were analysed by paper electrophoresis both in blood and urine at various intervals after administration of the compound. Protein-binding in plasma was determined by both electrophoresis and TCA precipitation. In vitro studies showed 30% uptake by red blood cells at equilibrium (30 min post-injection). 48% of the activity in the red cells could be removed after repeated washing with saline. The maximum uptake by myocardium occurred at 1 min and the maximal heart-to-blood ratios at 3 min. Although in vitro protein-binding was high, in vivo studies showed a very rapid plasma clearance (94% in 3 min) which indicated a weak binding. The amount of free iodine in plasma was less than 1% at any time after injection, thus not presenting a background problem or unnecessary radiation dose to thyroid and whole body. The major radioactive metabolites were 123I-p-hippuric acid and 123I-p-benzoic acid. In urine 123I-p-hippuric acid was excreted almost quantitatively. The metabolism was very fast, even 3 min post-injection the first metabolites could be found in the blood stream. Urinary excretion did not reach a plateau until 48 h. The total amount of radioactivity excreted was 56% within 48 h.