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Biomedical subjects

W A Breeman

Publications and source records attributed to W A Breeman.

At least 55 records · Page 3Linked to original sources
PubMed1994

A new radiolabelled somatostatin analogue [111In-DTPA-D-Phe1]RC-160: preparation, biological activity, receptor scintigraphy in rats and comparison with [111In-DTPA-D-Phe1]octreotide.

We have evaluated the potential usefulness of indium-111 labelled [DTPA-D-Phe1]RC-160, derived from the octapeptide somatostatin analogue RC-160, as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose 111In-and 115In-labelled [DTPA-D-Phe1]RC-160 was tested for its biological activity, and applied for somatostatin receptor scintigraphy in vivo to rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. We previously described the development of the 111In-labelled somatostatin analogue [DTPA-D-Phe1]octreotide and its use in the in vivo visualization of somatostatin receptor-positive tumours in rats and in humans. Like [111In-DTPA-D-Phe1]octreotide, [111In-DTPA-D-Phe1]RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours, and the tumours were clearly visualized by gamma camera scintigraphy. However, as compared to [111In-DTPA-D-Phe1]octreotide, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. Using this animal model we therefore conclude that [111In-DTPA-D-Phe1]RC-160 has no advantage over [111In-DTPA-D-Phe1]octreotide as a radiopharmaceutical in the visualization of somatostatin receptors which bind both analogues. However, recent reports suggest the existence of different somatostatin receptor subtypes on some human cancers, which differentially bind RC-160 and not octreotide. These tumours include cancers of the breast, ovary, exocrine pancreas, prostate and colon. [111In-DTPA-D-Phe1]RC-160 might be of interest for future use in such cancer patients as a radiopharmaceutical for imaging somatostatin receptor-positive tumours, which do not bind octreotide.

Animals↗
PubMed1993

Radioiodinated somatostatin analogue RC-160: preparation, biological activity, in vivo application in rats and comparison with [123I-Tyr3]octreotide.

We have evaluated the potential usefulness of the radioiodinated octapeptide RC-160, a somatostatin analogue, which might serve as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose, iodine-123 and iodine-125 labelled RC-160 was tested for biological activity and applied in vivo in rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. Our group has recently described the in vivo visualization of such tumours in rats and in humans with the radioiodinated somatostatin analogue [Tyr3]octreotide. Like [123I-Tyr3]octreotide, 123I-RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumors. However, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. We therefore conclude that in this animal model 123I-RC-160 has no advantage over [123I-Tyr3]octreotide as a radiopharmaceutical for the in vivo use as a somatostatin receptor imager, although, like [123I-Tyr3]octreotide, 123I-RC-160 shows specific binding to different somatostatin receptor-positive organs. Recently differences were reported in affinity between somatostatin and its analogues for somatostatin receptors expressed in different human cancers, like those of the breast, ovary, exocrine pancreas, prostate and colon. Therefore 123I-RC-160 might be of interest for future use in humans as a radiopharmaceutical for imaging octreotide receptor-negative tumours.

Animals↗
PubMed1993

Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients.

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

Humans↗
PubMed1993

Hepatobiliary handling of iodine-125-Tyr3-octreotide and indium-111-DTPA-D-Phe1-octreotide by isolated perfused rat liver.

Radiolabeled bioactive peptides may show receptor-mediated binding to tumors, making them suitable for scintigraphic imaging. The liver is an important organ for peptide clearance. To gain insight into the uptake and intracellular processing of somatostatin analogs, we compared the hepatobiliary handling of 125I-Tyr3-octreotide and 111In-DTPA-D-Phe1-octreotide, which are successfully used to image somatostatin receptor-positive tumors in vivo in isolated recirculating perfused rat livers. Sixty minutes following administration of the radiolabeled peptides, perfusion medium and biliary radioactivity were analyzed. Radioiodinated Tyr3-octreotide was rapidly cleared by the liver and 60% of the dose was excreted intact into the bile after 60 min. In contrast, 111In-DTPA-D-Phe1-octreotide was not cleared by the liver; medium radioactivity levels remained about constant and only 2% of the dose was found in the bile. These results are in agreement with in vivo findings in rats and humans. We concluded that isolated rat liver perfusion is a good system to rapidly gain insight into the hepatic handling of radiopharmaceuticals.

Animals↗
PubMed1992

Intracavitary brachytherapy of cystic craniopharyngiomas.

Visual function, endocrinological status, and radiological outcome are reported in 31 patients harboring a cystic craniopharyngioma, who underwent 35 intracavitary brachytherapy procedures with yttrium-90. In 26 of these patients intracavitary brachytherapy was the primary treatment. The follow-up period ranged from 2 to 80 months (41 +/- 22 months, mean +/- standard deviation). Five patients died from tumor-related causes. Endocrine recovery was modest. Prior to brachytherapy, visual acuity was diminished in 38 eyes and field defects were present in 46. Funduscopy before treatment revealed optic atrophy in 47% of the eyes. Visual acuity improved in 29% of the eyes studied, remained stable in 13%, and deteriorated in 58%. Visual field defects improved in 28% of the eyes studied, remained stable in 20%, and deteriorated in 52%. The possible causes for deterioration in visual function are discussed. Complete resolution of 10 cysts was noted. In 12 patients the size of the cyst decreased; however, in three of these patients new cyst formation took place. The cyst size stabilized in six cases and increased in three. Although there is still a substantial degree of visual function deterioration following intracavitary brachytherapy, morbidity is otherwise low, making this treatment modality a reasonable alternative to craniotomy.

Adolescent↗
PubMed1992

Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide.

Scintigraphy with 123I-Tyr-3-octreotide has several major drawbacks as regards its metabolic behavior, its cumbersome preparation and the short physical half-life of the radionuclide. The use of another radiolabeled analog of somatostatin, 111In-DTPA-D-Phe-1-octreotide, has consequently been proposed. DTPA-D-Phe-1-octreotide can be radiolabeled with 111In in an easy single-step procedure. DTPA-D-Phe-1-octreotide is cleared predominantly via the kidneys. Fecal excretion of radioactivity amounts to only a few percent of the administered radioactivity. For the radiation dose to normal tissues, the most important organs are the kidneys, the spleen, the urinary bladder, the liver and the remainder of the body. The calculated effective dose equivalent is 0.08 mSv/MBq. Optimal 111In-DTPA-D-Phe-1-octreotide scintigraphic imaging of various somatostatin receptor-positive tumors was obtained 24 hr after injection. In the six patients studied, tumor localization with 123I-Tyr-3-octreotide and with 111In-DTPA-D-Phe-1-octreotide were found to be similar. However, the normal pituitary is more frequently visualized with the latter radiopharmaceutical. In conclusion, 111In-DTPA-D-Phe-1-octreotide appears to be a sensitive somatostatin receptor-positive tissue-seeking radiopharmaceutical with some remarkable advantages: easy preparation, general availability, appropriate half-life and absence of major interference in the upper abdominal region, because of its renal clearance. Therefore, 111In-DTPA-D-Phe-1-octreotide may be suitable for use in SPECT of the abdomen, which is important in the localization of small endocrine gastroenteropancreatic tumors.

Adult↗
PubMed1991

Octreotide scintigraphy localizes somatostatin receptor-positive islet cell carcinomas.

Tyr-3-Octreotide is a synthetic derivative of somatostatin and a somatostatin-receptor analogue. The iodine-123-labelled compound localizes somatostatin-receptor-positive tumours. In this paper two patients are reported in whom somatostatin receptors were demonstrated in vitro. In a 60-year-old female with an islet cell carcinoma of the pancreas, multiple liver metastases and previously unrecognized bone metastases in the right acetabulum could be diagnosed as the reason for a persistent hypoglycaemia. In a 60-year-old male an islet cell carcinoma of the pancreas was localized with 123I-Tyr-3-octreotide. The somatostatin receptors were demonstrated in vitro and the tumour was successfully treated with somatostatin. These studies demonstrate that 123I-Tyr-3-octreotide offers the possibility of localizing somatostatin-receptor-positive tumours and their metastases. Moreover the method makes it possible to determine the receptor status of a tumour in vivo.

Adenoma, Islet Cell↗
PubMed1991

[111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation.

Somatostatin receptor-positive human tumors can be detected using radioiodinated analogues of somatostatin, both in vitro and in vivo. [123I-Tyr3]-octreotide has been successfully used in the visualization of somatostatin receptor-positive tumors by gamma camera scintigraphy, but this radiopharmaceutical has some major drawbacks, which can be overcome with other radionuclides such as 111In. As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201-995) was prepared. This peptide, [DTPA-D-Phe1]-octreotide (SDZ 215-811) binds more than 95% of added 111In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, [DTPA-D-Phe1]-octreotide and non-radioactive [115In-DTPA-D-Phe1]-octreotide. The binding of [111In-DTPA-D-Phe1]-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatostatin as well as by octreotide, suggesting specific binding of [111In-DTPA-D-Phe1]-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated [Tyr3]-octreotide, but indium-labeled [DTPA-D-Phe1]-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that [111In-DTPA-D-Phe1]-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.

Amino Acid Sequence↗
PubMed1991

In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats.

Radioiodinated somatostatin analogues are useful ligands for the in vitro and in vivo detection of somatostatin receptors. [111In-DTPA-D-Phe1]-octreotide, a somatostatin analogue labeled with a different radionuclide, also binds specifically to somatostatin receptors in vitro. In this study we investigated its in vivo application in the visualization of somatostatin receptor-positive tumors in rats. The distribution of the radiopharmaceutical was investigated after intravenous injection in normal rats and in rats bearing the somatostatin receptor-positive rat pancreatic carcinoma CA 20948. After injection the radiopharmaceutical was rapidly cleared (50% decrease in maximal blood radioactivity in 4 min), predominantly by the kidneys. Excreted radioactivity was mainly in the form of the intact radiopharmaceutical. Ex vivo autoradiographic studies showed that specific accumulation of radioactivity occurred in somatostatin receptor-containing tissue (anterior pituitary gland). However, in contrast to the adrenals and pituitary, the tracer accumulation in the kidneys was not mediated by somatostatin receptors. Increasing radioactivity over the somatostatin receptor-positive tumors was measured rapidly after injection and the tumors were clearly visualized by gamma camera scintigraphy. In rats pretreated with 1 mg octreotide accumulation of [111In-DTPA-D-Phe1]-octreotide in the tumors was prevented. Because of its relatively long effective half-life, [111In-DTPA-D-Phe1]-octreotide is a radionuclide-coupled somatostatin analogue which can be used to visualize somatostatin receptor-bearing tumors efficiently after 24 hr, when interfering background radioactivity is minimized by renal clearance. This is an advantage over the previously used [123I-Tyr3]-octreotide which has a shorter effective half-life and shows high abdominal interference due to its hepato-biliary clearance. Therefore, [111In-DTPA-D-Phe1]-octreotide seems a better alternative for scintigraphic imaging of somatostatin receptor-bearing tumors.

Animals↗
PubMed1991

In vivo use of a radioiodinated somatostatin analogue: dynamics, metabolism, and binding to somatostatin receptor-positive tumors in man.

Somatostatin analogues, labeled with gamma-emitting radionuclides, are of potential value in the localization of somatostatin receptor-positive tumors with gamma camera imaging. We investigated the application in man of a radioiodinated analogue of somatostatin, 123I-Tyr-3-octreotide, which has similar biologic characteristics as the native peptide. The radiopharmaceutical is cleared rapidly from the circulation (up to 85% of the dose after 10 min) mainly by the liver. Liver radioactivity is rapidly excreted into the biliary system. Until 3 hr after injection, radioactivity in the circulation is mainly in the form of 123I-Tyr-3-octreotide. Thereafter, plasma samples contain increasing proportions of free iodide. Similarly, during the first hours after injection, radioactivity in the urine exists mainly in the form of the unchanged peptide. Thereafter, a progressive increase in radioiodide excretion is observed, indicating degradation of the radiopharmaceutical in vivo. Fecal excretion of radioactivity amounts to only a few percent of the dose. The calculated median effective dose equivalent is comparable with values for applications of other 123I-radiopharmaceuticals (0.019 mSv/MBq).

Adult↗
PubMed1990

Receptor scintigraphy with a radioiodinated somatostatin analogue: radiolabeling, purification, biologic activity, and in vivo application in animals.

Radioiodinated Tyr-3-octreotide, a somatostatin analogue, is a useful ligand for the in vitro detection of somatostatin receptors. In this study, we have investigated the possible in vivo application of this radioligand in the detection of somatostatin receptor-bearing tumors by scintigraphy. The specific somatostatin-like biologic activity of radioiodinated Tyr-3-octreotide was confirmed in vitro: (a) radioiodinated Tyr-3-octreotide competes in the nanomolar range with specific receptor binding of somatostatin to suspended human meningioma membranes and (b) the secretion of growth hormone by cultured rat pituitary cells was similarly inhibited by iodinated Tyr-3-octreotide and somatostatin. In rats, intravenously injected 123I-Tyr-3-octreotide is rapidly cleared from the circulation mainly by the liver. Although this rapid clearance limits the amount of tracer available for somatostatin receptor-bearing tumors, the advantage of this rapid clearance is that the background level is rapidly reduced in favor of scintigraphic imaging of these tumors. Pancreatic tumors in rats were localized by scintigraphy after intravenous injection of 123I-Tyr-3-octreotide.

Animals↗
PubMed1989

Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin.

Various endocrine-related tumours contain large numbers of high-affinity somatostatin receptors. 123I-labelled tyr-3-octreotide (tyr-3-SMS 201-995, a synthetic derivative of somatostatin) was used to localise such tumours in vivo with a gamma-camera. Positive scans were obtained for two meningiomas, two gastrinomas, and one carcinoid; negative scans were obtained for one insulinoma (in which unlabelled octreotide had no effect on insulin levels), one phaeochromocytoma, one adrenal carcinoma (octreotide had no effect on cortisol levels), and three medullary thyroid carcinomas (octreotide had no effect on calcitonin levels). Thus radioiodinated tyr-3-octreotide can label somatostatin receptors in endocrine-related tumours in vivo and can therefore be used for tumour localisation.

Adult↗
PubMed1981

Comparative study of chylomicron and fatty acid utilization in small intestine and heart.

Chylomicrons were isolated from the urine of rats after a surgical procedure in which the cysterna chyli was connected with the right ureter. The fatty acids of the chylomicrons served as a respiratory substrate for rat heart and not for rat small intestine during in vitro vascular perfusions. The reason for the absence of chylomicron utilization in small intestine was found to be the virtual absence of lipoprotein lipase from this organ. Both heart and small intestine oxidized oleate complexed to albumin. Increasing the molar ratio of fatty acid to albumin from 3 to 6 did not affect the rate of fatty acid oxidation in heart, but increased fatty acid oxidation in small intestine.

Albumins↗
PubMedDate not supplied

Myocardial substrate utilization and hemodynamics following repeated coronary flow reduction in pigs.

The effect of repeated local ischemia and reperfusion on myocardial metabolism and ventricular performance was studied in 12 open-chested pigs fasted overnight. Myocardial ischemia was induced by reduction of the flow in the left anterior descending coronary artery to 40% of control during 30 min. After 35 min of reperfusion a second 30-min occlusion period was started, again followed by a 35-min reperfusion period. At the end of both reperfusion periods coronary flow and coronary resistance had returned to control values. During control there was lactate uptake, but no significant uptake of glucose, free fatty acids (FFA), triglycerdies, glycerol and inosine. During the first occlusion period the heart released lactate and inosine, and used glucose and FFA. At the end of the first reperfusion period lactate uptake approached control values, but inosine was still released by 10 of the 12 animals. In the second ischemic period, glucose and FFA were again taken up. Lactate and inosine were released, but the production was much smaller than during the first occlusion period. Depletion of myocardial glycogen and high-energy phosphates could be responsible for this quantitatively different response. Necrosis may have played a role, although enzyme release was minimal and only observed after the second occlusion period. Heart rate, peripheral resistance and ventricular filling pressure were virtually unchanged throughout the course of the experiments. Maximum rate of fall of left ventricular pressure (min LVdP/dt) decreased during ischemia and did not recover during reperfusion. Changes in min LVdP/dt and cardiac output were more closely related than changes in max LVdP/dt and cardiac output. This model cannot be used for the study of interventions during myocardial ischemia in which the animal serves as its own control.

Animals↗
PubMedDate not supplied

Internalization of [DOTA degrees,125I-Tyr3]Octreotide by somatostatin receptor-positive cells in vitro and in vivo: implications for somatostatin receptor-targeted radio-guided surgery.

We compared internalization of three radioiodinated octreotide (OCT) somatostatin (SS) analogs-[125I-Tyr3]OCT, [DTPA degrees, 125I-Tyr3]OCT, and [DOTA degrees,125I-Tyr3]OCT-by somatostatin receptor (SSR)-positive mouse AtT20 pituitary tumor cells and human insulinoma cells. The three SS analogs were internalized in a specific, time-dependent manner. Internalization was significantly inhibited by pertussis toxin (100 microg/l) by 38%, 43%, and 31%, and by an inhibitor of receptor-mediated endocytosis (phenyl arsine oxide; 10 microM) by 98%, 94%, and 92%, respectively. Binding affinities of the three radioligands were comparable (0.2, 0.2, and 0.3 nM, respectively). However, [DOTA degrees,125I-Tyr3]OCT was internalized in a five-fold higher amount in comparison with the two other radioligands. A comparably high uptake of [DOTA degrees, 125I-Tyr3]OCT was found in SSR-positive organs (pituitary, pancreas, and adrenals) in vivo in rats (a ten-fold, five-fold, and eight-fold higher uptake 4 hr post injection, respectively, compared with the two other radioligands). This resulted in very high target-background ratios for [DOTA degrees,125I-Tyr3]OCT 4 hr post injection amounting to 274, 566, and 623 in the pituitary, adrenals, and pancreas, respectively. Both in vivo and in vitro there was a rapid dissociation of radioactivity from the SSR-positive cells. Main conclusions are that: 1) coupling of chelating groups like DTPA or DOTA to the SS analog [Tyr3]OCT does not prevent the internalization of OCT after binding to SSRs; 2) [DOTA degrees, 125I-Tyr3]OCT is internalized in a significantly higher amount by AtT20 and human insulinoma cells and in vivo in rats in SSR-positive organs, in comparison with [DTPA degrees,125I-Tyr3]OCT and [125I-Tyr3]OCT; and 3) the very high target-background ratios in vivo make radioiodinated [DOTA degrees,Tyr3]OCT a very suitable ligand for SSR-targeted radioguided surgery of SSR-positive human neuroendocrine tumors.

Animals↗