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Tumour imaging radiopharmaceuticals.

32P, 131I-labeleed human serum albumin, 75Se-seleno-methionine, 107Hg-chlormerodrin, 67Ga-citrate and labelled bleomycin compounds, among others are discussed with particular respect to their observed clinical characteristics and suggested mechanisms of uptake. It is shown that there are striking similarities in the kinds of tumours demonstrable by these agents and that all of them may be taken up into inflammatory exudates. It is suggested that, while differences in the metabolism of each agent clearly exist, their mechanism of tumour uptake may be predominantly non-specific. It is concluded that radionuclide tumour imaging is of potential value mainly from the point of view of ease of whole body scanning for follow-up purposes and whereas other diagnostic methods may be more accurate in specific areas, ease of whole body screening is rarely a feature of these techniques. Methods for studying human cancer are necessarily restricted and the tumour imaging technique provides a unique, dynamic means of tumour observation. From the clinical point of view, the questions of why some tumours image well and others do not, what is the effect of treatment on uptake and how specific is the technique, are of most importance. In order to improve tumour imanging, more emphasis must be given to improving the lesion: background radioactivity ratio of the agents rather than attempting to improve detection equipment.

Animals↗

Comparison of 99mTc complexes for renal imaging.

The distribution of 17 different agents for renal imaging was compared in the rabbit by organ radioassay at 1 hr. Similarly, 99mTc complexes of iron-ascorbate, glucoheptonate (GHA) and 2,3-dimercaptosuccinic acid (DMS), and 203Hg-chlormerodrin were compared in the dog. The distribution of 99mTc-GHA and DMS was assessed in the human by blood and urinary clearance, external renal measurements, and scintillation camera imaging, and compared with older renal radiopharmaceuticals. Radiation dose estimates, based chiefly on human data, were calculated. Technetium-99m-DMS reaches a high concentration in the renal cortex and its urinary excretion rate and blood clearance are slow. It is excellent for imaging the renal parenchyma without activity in pelvocalyceal collecting system. However, it readily oxidizes and must be used within 30 min of preparation. The biologic distribution of 99mTc-GHA is similar to gluconate and iron-ascorbate complex. Its renal concentration is not as great as that of DMS but its blood and urinary clearances are much faster, resulting in lower radiation doses to most organs. Early camera images with this agent usually demonstrate both the renal parenchyma and collecting system. In later images, ther is excellent demonstration of the parenchyma alone, superior to that obtained with 99mTc-Sn-DTPA. It is a very stable complex and may be used for at least 5 hr after preparation. All radioactive renal agents examined to date have a significant concentration in the liver, making an accurate quantitative comparison between the two kidneys difficult.

Albumins↗

[Experimental investigations on the accumulation of radioactive compounds in autochtonal tumors in the rat (author's transl)].

For the first time results of investigations on rats with radioactive compounds in autochtonal tumors of the central nervous system, induced via placenta by Ethyl-Nitrose-Urea (ENU), are reported. In contrast to transplantation tumors the tumors induced by ENU are comparable in regard to the szintigrafic results with human brain tumors. The radiopharmaceuticals 131I-HSA, 99mTc-Pertechnetate, 203Hg-Chlormerodrin and 113m/111In-DTPA are similar to human brain tumors taken up by the ENU-tumors. For these findings it may be important, that the ENU-tumors are of neurogenic origin and do not differ histologically from the human brain tumors. The accumulation of the radioactive substances in ENU-tumors can be explained with the lesion at the blood-brain-barrier and at the blood-nerv-barrier. Therefore, it is discussed that the mechanism of the uptake is similar in human brain neoplasms and in ENU-tumors of the brain. The ENU-tumor model is suitable for testing new radiopharmaceuticals before their application in men.

Animals↗

Computer-assisted static/dynamic renal imaging: a screening test for renovascular hypertension?

Computer-assisted static/dynamic renal imaging with [197Hg] chlormerodrin and [99mTc]pertechnetate was evaluated prospectively as a screening test for renovascular hypertension. Results are reported for 51 patients: 33 with benign essential hypertension and 18 with renovascular hypertension, and for 21 normal controls. All patients underwent renal arteriography. Patients with significant obesity, renal insufficiency, or renoparenchymal disease were excluded from this study. Independent visual analyses of renal gamma images and time-activity transit curves identified 17 of the 18 patients with renovascular hypertension; one study was equivocal. There were five equivocal and three false-positive results in the essential hypertension and normal controls groups. The sensitivity of the method was 94% and the specificity 85%. Since the prevalence of the renovascular subset of hypertension is approximately 5%, the predictive value is only 25%. Inclusion of computer-generated data did not improve this result. Accordingly, this method is not recommended as a primary screening test for renovascular hypertension.

Adult↗

The 131-I ortho-iodohippurate photoscan in human renal allografts.

Nine examples, in seven patients, from a large cadaver renal allograft program, illustrate the value of radio-hippuran photoscans in differentiating causes of post-implant oliguria. Hippuran scans are shown to be more valuable than chlormerodrin scans when renal function is acutely depressed. Hippuran scans aided in the decision to remove kidneys in four cases of severe oliguria and to retain kidneys in two others. In two further examples, extravasation of urine was detected by scanning after radio-hippuran injection when other tests had failed to do so.The technique of radio-hippuran scanning has a place in the differentiation of acute and subacute renal dysfunction and has proved particularly valuable in the early oliguric complications of a cadaver renal transplant program.

Adult↗

The octanol/water distribution of mercury compounds.

Lipophilicity plays an important role in the biological action of mercurials. The distribution of one inorganic and five organic mercury compounds was determined in an n-octanol/water system. Lipophilicity decreased in the order CH3HgCl, bromomercurihydroxypropane, HgCl2, chlormerodrin, p-chloromercuribenzoic acid (PCMB), p-chloromercuriphenylsulfonic acid (PCMBS). The toxicity of mercurials, as reported in the literature, appears to parallel their lipophilicity.

Chemical Phenomena↗

Myocardial infarct imaging with technetium-labeled complexes.

Detection of acute myocardial infarction as an area of increased activity has intrigued investigators for some time. Initial attempts with 203Hg-chlormerodrin and 203Hg-fluorescein analogues were successful in man. More recently, however, successful imaging of the acute myocardial infarct has been achieved with several 99mTc complexes. A large group of radiotracers localize in acutely damaged tissue in various models of experimental infarction. From these data, a number of specific structural properties associated with infarct avidity have been identified; these include the presence of mercury and the structural configuration of the organic carrier.

Animals↗

Nuclear renal imaging in acute pyelonephritis.

Patients with acute pyelonephritis may present with a spectrum of clinical signs and symptoms. There are few noninvasive diagnostic studies, however, to confirm or exclude this diagnosis. A small number of patients, generally those with severe disease, will demonstrate radiographic changes on excretory urography, but the lack of sensitivity of the IVP in early, acute pyelonephritis is well documented. Several radionuclide techniques have been proposed to assist in the earlier detection of this clinical problem including imaging with Mercury-197 chlormerodrin, Gallium-67 citrate, Technetium-99m glucoheptonate. Technetium-99m DMSA, and, more recently, Indium-111 labeled white blood cells. The success of the renal cortical imaging agents as well as those which localize in infection are described in this report. There appears to be a complimentary role or the cortical imaging agents and the radiopharmaceuticals which localize in bacterial infection. Cortical agents offer the advantage of specific assessment of functioning renal tissue and a convenient, rapid method for following the response to treatment in a noninvasive manner. A pattern is described which may be diagnostic; correlation with Gallium-67 citrate of Indium-111 WBCs may increase the probability of infection as the cause for the cortical abnormality. The measurement of differential renal function using cortical agents provides additional information to assist the clinician in predicting the late effects of infection. Improved sensitivity and specificity, and a reproducible method for following the response to therapy in patients with acute pyelonephritis are the advantages of the techniques described.

Acute Disease↗

Inhibition by metals of a canine renal calcium, magnesium-activated adenosinetriphosphatase.

A number of metals were examined for inhibition of a canine renal calcium, magnesium-activated adenosinetriphosphatase (Ca2+, Mg2+-ATPase). Of the 27 metals investigated, only compounds of mercury, silver, gold, and uranium demonstrated 50% inhibition of the enzyme at concentrations lower than 10(-4) M. The order of inhibitory potency was Hg greater than Ag greater than U greater than Au. Organic mercury (chlormerodrin, mersalyl, p-chloromercuribenzoate) was less potent than inorganic mercuric chloride, but organic gold sodium thiomalate was equipotent with inorganic gold chloride. The inhibition produced by each metal decreased parallel to the decrease in enzyme activity, seen as the source of enzyme moved from the outer cortex inward to the papilla of the kidney. The regions of highest activity showed the greatest inhibition by each metal, and inhibition decreased as the control activity of the tissue decreased. This variability of inhibition was not related to the protein content of the enzyme preparation. As the ATP concentration increased, the inhibition produced by U was reduced; if the Mg (but not the Ca concentration) was increased while the ATP concentration remained constant, the inhibition increased. Changes in the Ca, Mg, and ATP concentrations did not alter the inhibition produced by Hg, Ag, and Au.

Animals↗

Organic mercurial diuresis: inhibition of glutamine utilization in the acidotic rat.

Organic mercurials inhibit mitochondrial glutamine metabolism in vitro while metabolic acidosis, a condition in which the predominant renal fuel is glutamine, potentiates mercurial diuresis. The following studies were undertaken to determine whether potentiation of diuresis reflects mercurial inhibition of glutamine utilization. (1) All three mercurials employed (mersalyl, chlormerodrin, and p-chloromercuribenzoate) are diuretics in the rat and this effect was potentiated by NH4Cl. (2) Despite reabsorbing less sodium, mercurial-treated rats had lower kidney ATP content (4.35 +/- 0.26 and 3.84 +/- 0.43 mumol/g dry weight (mercurial plus NH4Cl) than did controls (4.95 +/- 0.31 and 4.87 +/- 0.39 mumol/g dry weight (NH4Cl). (3) Isolated kidneys from NH4Cl and NH4Cl plus mercurial treated rats were perfused with 1 mM L-[U-14C]glutamine to determine rates of extraction and oxidation. Mercurial-treated acidotic rat kidneys had a reduced rate of glutamine uptake (40.8 +/- 7.4 vs. 64.8 +/- 5.8 mumol/h per kidney), a diminished rate of glutamine conversion to CO2 (14.8 +/- 3.6 vs. 26.4 +/- 5.2 mumol/h per kidney), and a reduction in glucose production (16 +/- 5 vs. 27 +/- 4 mumol/h per kidney). These results are consistent with an effect of organic mercurials upon glutamine utilization, limiting ATP availability, and thereby reducing tubular active sodium reabsorption.

Acidosis↗

[Study on tumor affinity of technetium-99m-labeled radiopharmaceuticals. (2) 99mTc-Sn-diphosphonate (99mTc-EHDP), 99mTc-Sn-dimercaptosuccinic acid (99mTc-DMSA), and 99mTc-Sn-diethyl stilbestrol diphosphate (99mTc-DSDP)].

The authors have examined the tumor affinity of various 99mTc-labelled radiopharmaceuticals to Ehrlich's tumor for the purpose of delineating positively human malignant neoplasm. This paper includes biologic distributions of 99mTc-Sn-diphosphonate (99mTc-EHDP), 99mTc-Sn-dimercaptosuccinic acid (99mTc-DMSA) and 99mTc-Sn-diethyl stilbestrol diphosphate (99mTc-DSDP, 99mTc-Honvan) as the second report on the tumor affinity to the Ehrlich-bearing mice. (a) Tumor concentration of 99mTc-EHDP was lowest and the positive delineation of implanted tumor with 99mTc-EHDP was poorest in sequential images, though the active accumulation to some soft tissue maglinant neoplasms, the breast cancer and the thyroid cancer, has been reported. (b) Tumor concentration and tumor to blood ratio of 99mTc-DMSA were not so high on the contrary of our expectation that 197Hg-DMSA may show the high tumor concentration and the high tumor to blood ratio like 197Hg chlormerodrin as same renal scanning radiopharmaceuticals. (c) Tumor concentration of 99mTc-DSDP was highest. Tumor to blood concentration ratio, however, was lower than that of the above mentioned radiopharmaceuticals but tumor to liver ratio and/or tumor to lung ratio was over 1.0 at the earlier time. Biologic distribution of 99mTc-DSDP was similar to that of 32P labeled DSDP and then it is presumed that 99mTc is labeled at phosphate ester of DSDP which is dephospholytated immediately by phospholylase in vivo following the intravenous injection. Therefore, it may be assumed that the accumulation mechanism of 99mTc-DSDP to Ehrlich's tumor is related to the phospholylase activity in neoplasms but is not known precisely.

Animals↗

A scintillation camera technique for quantitative estimation of separate kidney function and its use before nephrectomy.

A scintillation camera technique was used for measuring renal uptake of [131I]Hippuran 80-110 s after injection. Externally measured Hippuran uptake was markedly influenced by kidney depth, which was measured by lateral-view image after injection of [99mTc]iron ascorbic acid complex or [197Hg]chlormerodrine. When one kidney was nearer to the dorsal surface of the body than the other, it was necessary to correct the externally measured Hippuran uptake for kidney depth to obtain reliable information on the true partition of Hippuran between the two kidneys. In some patients the glomerular filtration rate (GFR) was measured before and after nephrectomy. Measured postoperative GFR was compared with preoperatively predicted GFR, which was calculated by multiplying the preoperative Hippuran uptake of the kidney to be left in situ, as a fraction of the preoperative Hippuran uptake of both kidneys, by the measured preoperative GFR. The measured postoperative GFR was usually moderately higher than the preoperatively predicted GFR. The difference could be explained by a postoperative compensatory increase in function of the remaining kidney. Thus, the present method offers a possibility of estimating separate kidney function without arterial or ureteric catheterization.

Adult↗

Ouabain-sensitive adenosine triphosphatase from human kidneys.

Adenosine triphosphatase (ATPase) was studied in tissue homogenates and subcellular fractions derived from human cadaver kidneys maintained in an organ preservation unit for transplantation. The activity of ouabain-sensitive ATPase was highest in the medulla, intermediate in the cortex and lowest in the papilla, The cortical enzyme activity diminished with time during maintenance perfusion of the kidneys. Similar concentrations of K+, Na+, Mg++, ATP and MgATP were required for half-maximal rates of ouabain-sensitive ATPase activity from the cortex or the medulla. The sensitivity of the enzyme to ouabain from both parts of the kidney was similar. K+ antagonized inhibition of the enzyme by ouabain. Chlormerodrin, mersalyl, mercaptomerin and ethacrynic acid were inhibitors of the enzyme.

Adenosine Triphosphatases↗

Oubain-sensitive adenosine triphosphatase from human kidneys.

Adenosine triphosphatase (ATPase) was studied in tissue homogenates and subcellular fractions derived from human cadaver kidneys maintained in an organ preservation unit for transplantation. The activity of ouabain-sensitive ATPase was highest in the medulla, intermediate in the cortex and lowest in the papilla. The cortical enzyme activity diminished with time during maintenance perfusion of the kidneys. Similar concentrations of K+, Na+, Mg++, ATP and MgATP were required for half-maximal rates of ouabain-sensitive ATPase activity from the cortex or the medulla. The sensitivity of the enzyme to ouabain from both parts of the kidney was similar. K+ antagonized inhibition of the enzyme by ouabain. Chlormerodrin, mersalyl, mercaptomerin and ethacrynic acid were inhibitors of the enzyme.

Adenosine Triphosphatases↗

Comparison of renal extraction efficiencies for radioactive agents in the normal dog.

The renal extraction efficiencies for various radioactive agents were measured in normal anesthetized dogs during 1 hr after a single intravenous injection. Radioassays were made on serial blood samples drawn simultaneously from the aorta upstream from the renal arteries and from one renal vein. As a reference substance [131I]o-iodohippurate was injected concurrently in all experiments. Blood clearances from serial venous samples and urinary excretion also were measured. Extraction efficiency from whole blood was calculated as (A-V) divided by A, where A = aortic concentration and V = renal venous concentration. This ratio for commercial [131I]o-iodohippurate fell steadily from 88% at 30 sec to 50% at 1 hr. For "purified" [131I]o-iodohippurate the fall was less marked, to 61% at 1 hr. The EE ratios for all other agents were stable after the first minute. The Tc-99m complexes of DTPA, glucoheptonate, and acetylcysteine had ratios averaging 27-29%. The ratios of Tc-99m DMS and Hg-197 chlormerodrin had much lower average values of 8 and 14%, respectively. None of the newer agents approached the extraction efficiency of [131I]o-iodohippurate.

Animals↗

The value of sequential scanning in the detection of metastatic tumors.

The usefulness of sequential scanning, three and 24 hours after injection of 197Hg chlormerodrin in the detection of metastatic tumors of the brain has been demonstrated. The 24-hour scan was positive in 29% of the cases in which a metastatic lesion was suspected although the three-hour scan was negative, and the 24-hour scan also revealed additional masses in another 20%. The delayed scan helped to demarcate the actual location of the lesion in 24% of the cases in which the three-hour scan was graded merely suspicious. It is concluded that the addition of a 24-hour scan strongly reinforces the statistical accuracy of the 197Hg brain scan, and thus is of practical clinical importance.

Brain Neoplasms↗