P. Angelberger

Vasoactive Intestinal Peptide-Receptor Imaging for the Localization of Intestinal Adenocarcinomas and Endocrine Tumors

Background Intestinal adenocarcinomas and various endocrine tumors express large numbers of high-affinity receptors for vasoactive intestinal peptide (VIP). We have evaluated the usefulness of scanning with VIP labeled with iodine-123 for tumor localization in patients with gastrointestinal tumors. Methods Radioiodinated VIP was purified by high-pressure liquid chromatography and administered as a single intravenous bolus injection (300 pmol [1 microgram]). Scanning with radiolabeled VIP was compared with computed tomography and scanning with somatostatin analogues in 79 patients with colorectal cancer, pancreatic carcinoma, gastric cancer, carcinoid tumor, or insulinoma. Results Visualization of gastrointestinal tumors and metastases was obtained with radiolabeled VIP. Binding of the labeled peptide by primary tumors and metastases was visible shortly after the injection and was still demonstrable at 24 hours. In patients with colorectal adenocarcinomas, primary or recurrent tumors were visualized in 10 ...

Characterization of 123I-vascular endothelial growth factor–binding sites expressed on human tumour cells: Possible implication for tumour scintigraphy

To explore the possibility of vascular endothelial growth factor (VEGF) receptor scintigraphy of primary tumours and their metastases, we analysed the binding properties of 123I‐labelled VEGF165 (123I‐VEGF165) and 123I‐VEGF121 to human umbilical vein endothelial cells (HUVECs), several human tumour cell lines (HMC‐1, A431, KU812, U937, HEP‐1, HEP‐G2, HEP‐3B and Raji), a variety of primary human tumours (n = 40) and some adjacent non‐neoplastic tissues as well as normal human peripheral blood cells in vitro. Two classes of high‐affinity 123I‐VEGF165‐binding site were found on the cell surface of HUVECs. In contrast, one class of high‐affinity binding sites for 123I‐VEGF165 was found on HMC‐1, A431, HEP‐1, HEP‐G2, HEP‐3B and U937 cells as well as many primary tumours. For 123I‐VEGF121, a single class of high‐affinity binding site was found on certain cell lines (HUVEC, HEP‐1 and HMC‐1) and distinct primary tumours (primary melanomas, ductal breast cancers and ovarian carcinomas as well as meningiomas). Tumour cells expressed significantly higher numbers of VEGF receptors compared with normal peripheral blood cells and adjacent non‐neoplastic tissues. Immunohistochemical staining revealed that the VEGF receptor Flk‐1 is expressed to a much higher extent within malignant tissues compared with neighbouring non‐neoplastic cells. We observed significantly greater specific binding of 123I‐VEGF165 and 123I‐VEGF121 to a variety of human tumour cells/tissues compared with the corresponding normal tissues or normal peripheral blood cells. In comparison with 123I‐VEGF121, 123I‐VEGF165 bound to a higher number of different tumour cell types with a higher capacity. Thus, 123I‐VEGF165 may be a potentially useful tracer for in vivo imaging of solid tumours.

Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage

The monitoring of local vascular kinetics after injection of autologous radiolabelled low-density lipoprotein (LDL) allows characterization of human atherosclerotic lesions as to the presence of foam cells and the quality of endothelial coverage. The following evidence exists: (1) dynamic imaging reveals two types of visual LDL accumulation in the vascular bed, one increasing, becoming visible sometimes only as late as after 24 h, and the other one appearing very early on, but decreasing with time; (2) the accumulation of iodine-123 LDL or iodine-131 LDL in the vascular bed shows three major types of local kinetic curves, which correlate with scintigraphic findings; (3) the accumulation of radiolabelled LDL in the vascular bed of humans in vivo is similar to its uptake in de- and re-endothelialized vessels of experimental animals using 125I-LDL; (4) morphological control in endarteriectomy samples confirms the hypothesis that this promising new approach may for the first time allow the in vivo monitoring of preclinical lesions in humans.

Imaging of human atherosclerotic lesions using 123I-low-density lipoprotein

In patients suffering from clinically manifest atherosclerosis autologous LDL-labelling has been done using 123I. This technique allows localization of areas with an increased LDL entry as well as a monitoring of kinetics. Normally, no tracer uptake can be seen in the vascular system. Positive camera images, however, can be obtained in pathological areas as early as 60 min after LDL-reinjection. Experimental data and morphological control reveal a very good correlation to the gamma-camera findings. The technique seems to be very promising for diagnosis in patients suffering from atherosclerosis and hyperlipoproteinemia.

The use of 123I-labeled heptadecanoic acid (HDA) as metabolic tracer: Preliminary report

The feasibility of using 123I-heptadecanoic acid (HDA) as a metabolic tracer was studied. Different administration routes of HDA were compared. An intracoronary bolus injection was given to calves (n=3), and an intravenous injection was given to patients (n=4). In addition, we examined the influence of 4-h halothane anesthesia in calves and in patients the impact of an insulin (1.5 IU/kg)+ glucose (1.5 g/kg) infusion on the myocardial kinetics of HDA. Data were accumulated with a scintillation probe in calves (t=50 min) and a gamma camera in patients (t=70 min). In calves after an intracoronary bolus injection of HDA the myocardial time-activity curve could be described by two exponentials. The mean elimination halftime of the initial phase (ta 1/2) was 7.3 min and that of the second phase (tb 1/2) was 35 min. The ratio of the size of the initial and second component at to was 0.93. Halothane anesthesia prolonged the elimination half-times and reduced the component ratio. The biphasic behavior of the myocardial time-activity curve was maintained in patients after intravenous administration of HDA under basal conditions (initial ta 1/2=8.4 min). However, during infusion of insulin+glucose the decline in the myocardial activity was prolonged and monoexponential. This data shows that insulin glucose, interfering with fatty acid metabolism, influences the myocardial washout of HDA, and thus support its use as a metabolic tracer.

Evaluation of 99mTc-dichloro bis (1,2-dimethylphosphino) ethane (99mTc-DMPE) for myocardial scintigraphy in man

Abstract99mTc-DMPE was used for myocardial scintigraphy in ten patients with coronary artery disease. As in 201Tl studies regional activity of 99mTc-DMPE was reduced in infarcted myocardium. However, activity accumulation of 99mTc-DMPE in the heart was faint, while that in the liver was prominent. The activity ratio of heart to liver improved with time, whereas that of heart to lung decreased. The scintigraphic quality was considerably worse in 99mTc-DMPE studies than in those with 201Tl, due to high background activity. Also the visualization of the ribs and sternum interfered with the interpretation of the scintigrams. From these results it appears that 201Tl remains still the agent of choice for myocardial perfusion scintigraphy.

Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage

The entry of autologous iodine-125 low density lipoprotein (125I-LDL) into the aortic wall in rabbits was measured. After abdominal endothelium abrasion with a Fogarthy catheter the animals were fed a 1% cholesterol-supplemented diet for 4 weeks. The animals were killed 1–48 h after administration of 25 μCi 125I-LDL. Local entry of radiolabelled LDL was estimated and correlated to endothelial surface lining and foam cell content, both controlled morphologically. Endothelialized segments showed the lowest entry of 125I-LDL, the maximum uptake was reached at around 8 h. In deendothelialized segments the entry was higher and the peak later (12 h), while in re-endothelialized segments a continuous increase in 125I-LDL entry up to 48 h was measured. Number and extent of foam cells correlated with the entry of LDL. The data indicate the usefulness of LDL radiolabelling for qualitative in vivo information on surface lining and foam cell content.

Prostaglandin E1 decreases the low‐density‐lipoprotein entry into rabbit arterial wall

1 In 72 male rabbits fed a 1% cholesterol supplemented diet the effect of a 4 weeks daily infusion of prostaglandin E1 (PGE1, 20 μg kg−1min−1 over 2 h) on [125I]‐low density lipoprotein (LDL) accumulation (10 μCi; 0.5 mg protein ml−1) was examined versus sham‐treatment after removal of the endothelium of the abdominal aorta by a Fogarthy catheter. 2 The uptake of [125I]‐LDL was significantly (P < 0.01) higher in endothelium‐free aortic segments (showing the highest peak maximum at around 12 h after 125I‐injection) as compared to aortic segments with endothelium intact (showing the lowest uptake of [125I]‐LDL with the peak maximum at 48 h, last control time). Segments with the endothelium restored showed a similar LDL‐retention curve to segments with endothelium however, being again significantly (P < 0.01) higher. 3 PGE1‐treatment caused reduction in LDL‐accumulation, being significantly (P < 0.001) pronounced in segments without endothelium and in segments with endothelium restored. 4 The findings indicate a beneficial effect of PGE1 in lipid metabolism by decreasing the LDL‐influx into the arterial wall in‐vivo.

Technetium-99m labelled LDL as a tracer for quantitative LDL scintigraphy

The goal of the present study was to optimize technetium-99m labelling of low-density lipoprotein (LDL) and to investigate the in vitro and in vivo properties of the tracer to determine whether its application for quantitative scintigraphy of hepatic LDL receptor activity is feasible. LDL labelled with iodine-125 by the iodine monochloride method was used as a reference tracer. Comparison of different assessments of radiochemical purity [trichloro-acetic acid precipitation (%ppTCA), paper chromatography, size-exclusion chromatography and chloroform-methanol extraction] exhibited %ppTCA to be superior as a parameter of tracer quality. In spite of a high radiochemical purity immediately after labelling, modifications of 99mTc labelling of LDL did not overcome the poor long-term stability of the tracer. Subsequent dialysis in phosphate buffer over about 3 h sufficiently increased the long-term stability in vitro and in vivo. The competitive recognition of dialysed 99mTc-LDL and 125I-LDL with native LDL by high-affinity binding sites was demonstrated in human hepatoma cells (HepG2) and human fibroblasts. Biodistribution data of simultaneously injected 99mTc-LDL and 125I-LDL in New Zealand White rabbits showed a high uptake of both tracers in tissues with high LDL receptor activity, yet 99mTc-LDL uptake exceeded 125I-LDL uptake by two- to sevenfold. In contrast to 125I-LDL, 99mTc-LDL showed a higher unspecific uptake into the bone marrow and the spleen, suggesting an additional uptake mechanism probably via the scavenger pathway. Curve deconvolution of plasma clearance in five female New Zealand White rabbits and five male hyperlipidaemic patients again showed a marginally different biokinetic behaviour of 99mTc-LDL and 125I-LDL. It is concluded that dialysis of 99mTc-LDL substantially increases long-term stability, which is essential for quantification purposes, and that the dialysed tracer has retained its biological integrity as it is recognized by the LDL receptor in vitro. It remains to be determined to what extent the estimation of hepatic LDL receptor activity by quantitative 99mTc-LDL scintigraphy is influenced by the different biokinetic behaviour of 99mTc-LDL and 125I-LDL.

Isradipine, a calcium-entry blocker, decreases vascular (125-I)low-density lipoprotein entry in hypercholesterolemic rabbits

In 72 male rabbits aged 6 months, the endothelium of the abdominal aorta was abraded by a Fogarthy catheter. The animals were then fed a cholesterol-supplemented diet for 4 weeks. In addition, half of the animals were treated for the entire period with isradipine (0.3 mg kg daily dihydropyndine calcium antagonist: the other 36 aminuals served as controls. One hour and 3.6 12. 24. and 48 hours before the animals were killed. [125-I]low-density lipoprotein (1.1)1.10 μ was administered intravenously (i.v. to siv animals in each group. The [125-I]LDL entry was quantified in the abdominal aorta according to the type and presence of endothelial lining. Isradipine significantly reduced the {125-I]LDL entry at most time intervals. In parallel, an increase in vascular prostaglandin (PGL) synthesis was noted, which might be the underlying mechanism for the decreased LDL entry.