Mechanism of tumor and liver concentration of 111In and 169Yb: 111In and 169Yb binding substances in tumor tissues and liver

Tumor-bearing animals were injected with ¹¹¹In- and ¹⁶⁹Yb-citrate. Tumor homogenates, from which the nuclear fraction was removed, and the mitochondrial fractions of the host livers were digested with pronase P. After digestion, the supernatants of the reaction mixtures were applied to Sephadex G-100 columns. The resultant eluates were analyzed for radioactivity, protein, uronic acid, and sialic acids. Three peaks of radioactivity were obtained by gel filtration. The first peak, eluted in the void volume, contained a species whose molecular weight exceeded 40000. The second peak consisted of substances with molecular weights of 9400–40000. Radioactivity in the third peak was liberated ¹¹¹In and ¹⁶⁹Yb. These two nuclides in the second peak were bound to acid mucopolysaccharide and/or the sulfated carbohydrate chain of sulfated glycoprotein. It was thought that the nuclides in the first peak might be bound to some acid mucopolysaccharides.The second peak nuclides seemed to be bound to acid mucopolysaccharide that contained no uronic acids, and/or to the sulfated carbohydrate chain of sulfated glycoprotein. It was concluded that they were bound to the acid mucopolysaccharides and/or the sulfated carbohydrate chain of sulfated glycoprotein in tumor tissues and liver lysosomes.     

Mechanism of tumor and liver concentration of 111In and 169Yb: 111In and 169Yb binding substances in tumor tissues and liver

Tumor-bearing animals were injected with 111In- and 169Yb-citrate. Tumor homogenates, from which the nuclear fraction was removed, and the mitochondrial fractions of the host livers were digested with pronase P. After digestion, the supernatants of the reaction mixtures were applied to Sephadex G-100 columns. The resultant eluates were analyzed for radioactivity, protein, uronic acid, and sialic acids. Three peaks of radioactivity were obtained by gel filtration. The first peak, eluted in the void volume, contained a species whose molecular weight exceeded 40 000. The second peak consisted of substances with molecular weights of 9400-40 000. Radioactivity in the third peak was liberated 111In and 169Yb. These two nuclides in the second peak were bound to acid mucopolysaccharides and/or the sulfated carbohydrate chain of sulfated glycoprotein. It was thought that the nuclides in the first peak might be bound to some acid mucopolysaccharides. The second peak nuclides seemed to be bound to acid mucopolysaccharide that contained no uronic acids, and/or to the sulfated carbohydrate chain of sulfated glycoprotein. It was concluded that they were bound to the acid mucopolysaccharides and/or the sulfated carbohydrate chain of sulfated glycoprotein in tumor tissues and liver lysosomes.     

Subcellular distribution of gallium-67 in tumor and liver

Subcellular distribution of ⁶⁷Ga was quantitatively determined to evaluate the role of the lysosome in accumulation of ⁶⁷Ga in malignant tumor tissue and the liver using three different tumor models and the host liver. In Yoshida sarcoma and Ehrlich tumor, most of the radioactivity of ⁶⁷Ga was localized in the supernatant fraction, and only a small amount of radioactivity was localized in the mitochondrial fraction, which contains lysosomes. In the liver, however, most of the radioactivity was concentrated in the mitochondrial fraction. The radioactivity of this fraction increased with time after the administration of ⁶⁷Ga and reached approximately 50% of total radioactivity within 24 h. In the case of hepatoma AH 109A, radioactivity of the mitochondrial fraction increased with time after administration, and about 30%, of total radioactivity was concentrated in this fraction after 24 h. It is concluded that lysosome does not play a major role in the tumor concentration of ⁶⁷Ga, although it may play an important role in the liver concentration of ⁶⁷Ga. In the case of hepatoma AH109A, it is presumed that lysosome plays a considerably important role in the tumor concentration of ⁶⁷Ga, hepatoma AH 109A possessing some residual features of the liver.     

Subcellular kinetics of In-111 monoclonal antibody in the liver

To evaluate the mechanism for prolonged retention of In-111 monoclonal antibody (MoAb) by the liver, we investigated the subcellular kinetics of the In-111 225.28S, an antimelanoma IgG2a. Forty microCi/10 micrograms of the In-111 MoAb was injected IV into groups of SD rats. The liver was excised at 3, 8, 17, 24, 48 and 72 hr and homogenized with 0.25 M sucrose containing 0.01 M Tris-HCl buffer (pH 7.6). Subcellular fractionation was carried out by 3-step (ultra-)centrifugation. The radioactivity of each fraction including nuclear, mitochondrial (lysosomal), microsomal and supernatant fraction was measured and expressed as a percentage of the total radioactivity of all the fractions. Moreover, the supernatant fraction was assessed by size exclusion HPLC. The supernatant was a predominant fraction of the In-111 radioactivity, 61% at 3 hr, and was decreased with time, 21% at 72 hr (p less than 0.01), while the activity in the mitochondrial fraction continued to increase from 11% to 44%. As compared to these two fractions, the nuclear and microsomal radioactivities were relatively constant, 10-25%, throughout the study. The HPLC analysis revealed that the supernatant In-111 activity at early time points was mainly eluted with an intact IgG and thereafter this major peak activity was reduced with associated activity peaks found in smaller moiety fractions. To compare the In-111 MoAb with the iodine labeled MoAb, we also investigated the subcellular kinetics of the I-125 MoAb in the same manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Standardization and decay data of 169Yb

The specific activity of a ¹⁶⁹Yb solution was determined at the PTB by 4πEC-γ-coincidence measurements and by 4πγ-counting with a relative standard uncertainty of 0.1%. Based on a simplified decay scheme with 21 gamma transitions, relative gamma-ray emission probabilities measured at the PTB and data from other authors, a consistent set of decay data for the decay of ¹⁶⁹Yb was calculated. The absolute emission probability of the 198 keV gamma rays was determined to be (0.3591±0.0013) photons per disintegration.     

Evaluation of 169Yb decay data.

This evaluation of the complete decay scheme of 169Yb sums up the recent measurements carried out during an international exercise in which 11 laboratories were involved, and also takes into account other independent experiments. As a result of the numerous high-quality measurements available, the decay scheme is shown to be highly consistent. The half-life is determined to be 32.018 (5)d, and the emission probabilities of the two reference gamma lines of 198 and 307 keV are recommended to be 35.93 (12)% and 10.046 (45)%, respectively.     

In vivo migration of 111In radiolabeled mouse-spleen lymphocytes and tumor cells

Mouse-spleen lymphocytes, mouse mammary adenocarcinoma cells (MMA-67) and mouse lymphoma cells (S49.1) were radiolabeled with 111In and their in vivo migration patterns studied over a 24-72 h period after i.v. injection into syngeneic mice. All three cell lines showed different in vivo migration patterns. Initially, some trapping of the cells occurred in the lungs at 15 min. More MMA-67 cells were initially trapped in the lungs than S49.1 cells or lymphocytes. At 24 h, most of the 111In labeled cells had left the lungs and accumulated in various tissues and organs. At 48 and 72 h, only slight changes in the localization patterns of the 111In radiolabeled cells in vivo were noted when compared to the 24 h patterns. About 35% of the injected 111In was excreted from the animals over the 72 h period of these experiments. In vitro studies compared the growth and/or viability of 111In radiolabeled lymphocytes or tumor cells to nonradiolabeled lymphocytes or tumor cells. The percentage of 111In released from the cells in culture was also determined. Similar values for growth and/or viability were obtained between non-radiolabeled cells and MMA-67 cells radiolabeled with 1.35 dpm 111In per cell; S49.1 cells, 0.51 dpm111In per cell; and lymphocytes, 0.04 dpm 111In per cell.     

Absolute measurements of photon emission probabilities of 169Yb.

A solution of 169Yb was absolutely standardized by the 4pi(EC,X)-gamma coincidence counting method and the result was used to obtain direct measurements of gamma-ray emission probabilities with a coaxial HPGe detector. The empirical relation proposed by (Va?o, F., Gonzalez, L., Gaeta R., Gonzalez, J.A., 1975. An empirical function which relates the slope of the Ge efficiency curves and the active volume Nucl. Instr. Meth. 123, 573) was tested using the gamma spectral response above 200 keV. The half-life of 169Yb was also measured with a 4pi gamma ionization chamber.     

Results from the EUROMET action 410 concerning the decay data of 169Yb

An international comparison EUROMET, action No. 410, was organized with the objective of improving the knowledge of nuclear data for ¹⁶⁹Yb decay. To determine the photon emission probabilities, the participants were asked to measure at least one of the quantities, activity per unit mass and/or photon emission rate per unit mass. In addition, the participants were requested to report the count rates observed with point source samples for an eventual coaxial-type germanium detector characterization. Eleven laboratories participated, giving one or more sets of results. In all, 34 sets of results were received, 17 for the activity measurement, 11 for the photon emission rate measurement and six for the detector characterization.Using the accurate activity value obtained from this exercise, it was possible to determine the emission probabilities of the main X- and γ-rays with an uncertainty of 1–2% for the LX-rays, 1 % for the KX-rays and ≤0.5% for the main γ-rays. These data can be very useful for the calibration of so-called ‘γ–X ray detectors’. The measurement of ¹⁶⁹Yb with type P or N coaxial structure detectors has also made possible an estimation of their diameters and volumes.     

Distribution of 169Yb microspheres and colloidal 198Au following injection into the rectal submucosa in dogs

A comparison between two tracers, the one colloidal suspension of 198Au, the other 169Yb-labelled microspheres of 8 to 10 micron has been made concerning lymphatic and hematogenous spread from the submucosa in the rectum in dogs. Both tracers have, in principal, the same distribution. It was therefore considered that a colloidal suspension of 198Au is a useful tracer for functional anatomic investigations of lymph drainage.     

Activation cross sections of the 169Tm(d,2n) reaction for production of the therapeutic radionuclide 169Yb.

Activation cross sections of deuteron induced nuclear reactions on (169)Tm were measured up to 20 MeV by using the stacked-foil technique. Special emphasis was on production of the internal radiotherapy related radionuclide (169)Yb. No earlier experimental cross-section data on deuteron induced reactions on (169)Tm were found in the literature. The experimental data were compared with the results of the nuclear model codes ALICE-IPPE and EMPIRE-II. The integral yield of the (169)Tm(d,2n)(169)Yb reaction was deduced over the optimum energy range Ed = 20-->9 MeV. At 3.8 MBq/microA.h the yield is lower than that available from the commonly used (168)Yb(n,gamma) (169)Yb reactor method but on the other hand, it is higher than the yields from the earlier investigated (169)Tm(p,n)(169)Yb and (nat)Er(alpha,x) (169)Yb reactions.     

Early massive accumulation of In-111 pentetreotide in a metastatic liver tumor of islet cell carcinoma

A 62-year-old woman was examined with In-111 pentetreotide and Ga-67 citrate. She had undergone an operation to resect a neuroendocrine tumor of the pancreas and still had masses in the liver. One of her hepatic lesions had been biopsied and acinar cell carcinoma was suspeted. Fluid in the cyst of the tumor, however, contained a high concentration of gastrin and the tumor was strongly suspected of being a metastasis from the neuroendocrine tumor of the pancreas. The hepatic tumors quickly accumulated In-111 pentetreotide immediately after the injection, but there was no Ga-67 citrate uptake in the tumor. Five months after pentetreotide scintigraphy, her hepatic tumors were resected and histologically proven to be metastasis of islet cell carcinoma. In-111 pentetreotide provides information of the somatostatin-receptor status on the tumor and supports the diagnosis made by hormonal survey.     

The uptake of 111In in the liver and bone marrow of partially hepatectomized and venesectioned rats.

Indium-111 ((111)In) has a strong binding affinity for transferrin (Tf), and the (111)In-Tf complex binds to Tf receptor in various tissues. In partial hepatectomy (PH), a part of blood in circulation is lost along with removed liver tissues; consequently, the number of blood cells and the amount of Tf in circulation decreases. These decreases should greatly affect the uptake of (111)In in the liver and bone marrow. In order to investigate this effect, we compared the uptake in partially hepatectomized rats with that in venesectioned rats, in which only the volume of blood in circulation had been decreased. Our data show that fewer blood cells and smaller amount of Tf in circulation due to venesection increased the uptake of (111)In in bone marrow, but not in the liver, whereas PH increased the uptake of (111)In in both bone marrow and liver. The higher bone marrow uptake of (111)In must be related to the increase of the hematopoietic function resulted from the smaller amount of blood; the higher uptake in liver may be closely related to liver regeneration.