Distribution of 95Zr and 181Hf in tumor-bearing animals and mechanism for accumulation in tumor and liver

Tumor uptake rates, concentrations in the mitochondrial fraction (containing lysosome) of liver and tumors, avid accumulations in connective tissue (especially inflammatory tissue) and binding substances in these tissues of ⁹⁵Zr and ¹⁸¹Hf were essentially similar to those for ⁶⁷Ga, ¹¹¹In, ¹⁶⁹Yb and ¹⁶⁷Tm. However, the main binding substance of the above elements in group IV in tumor and liver was acid mucopolysaceharide whose molecular weight exceeded 40,000, although the above elements in group III were bound mainly to the acid mucopolysaccharide with a molecular weight of about 10,000.     

Rhodanese and ALA-S in mammary tumor and liver from normal and tumor-bearing mice.

1. Basal levels and allyl-isopropylacetamide (AIA) or veronal induced levels of delta-amino-levulinate synthetase (ALA-S), cytoplasmic and mitochondrial rhodanese were determined in tumor (T) and liver of both normal mice (NM) and T-bearing mice (TBM). 2. Rhodanese tumoral mitochondrial levels were higher than the hepatic normal mitochondrial fraction, while the cytoplasmic activity was nearly equal in all sources. 3. In neither case was the activity of tumoral ALA-S and rhodanese altered by any of the porphyrinogenic drugs. 4. Mitochondrial and cytoplasmic rhodanese activity was also measured in tumor and liver of TBM at different intervals after transplantation. We concluded that the behaviour of rhodanese is a property inherent to the tissue and not one attained with time.     

On the mechanism of ethanol-induced accumulation of triglycerides in the liver

The possibility that ethanol or acetaldehyde has a direct effect on the activity of acyl-CoA-ligases or $\text{sn}$-glycerophosphate acyltransferases or on the biosynthesis of phosphatidic acid and triglycerides from free fatty acids was studied with subcellular preparations from rat liver. No stimulatory effect of ethanol or acetaldehyde could be observed in any case. It was further shown that the microsomal fraction of homogenate of livers of rats treated with ethanol (single peroral dose of 4.5 g of ethanol per kg body weight) did not have an increased capacity to biosynthesize phosphatidic acid. The possibility was excluded that excess cofactors necessary for formation of phosphatidic acid are responsible for the higher accumulation of triglycerides in livers of rats treated with ethanol.The results indicate that the increased formation of triglycerides in liver of rats treated with ethanol is not due to increased activity of acyl-CoA-ligase or $\text{sn}$-glycerophosphate acyltransferase or due to increased availability of $\text{sn}$-glycerophosphate, ATP or CoA-SH. It is suggested that increased availability of fatty acids is the major explanation for the increased accumulation of triglycerides in the liver after ethanol administration.     

Biodistribution and tumor localization of lymphokine-activated killer T cells following different routes of administration into tumor-bearing animals

The efficiency of adoptive cellular immunotherapy of cancer might depend on the number of effector cells that reach the malignant tissues. In the present study, the biodistribution and tumor localization of ex vivo lymphokine-activated T killer (T-LAK) cells was investigated. Methods: T-LAK cells were labeled with ¹²⁵I-dU or the fluorescent dye tetramethylrhodamine isothiocyanate (TRITC) and transferred by intravenous, -cardiac, -portal or -peritoneal injection into normal (C57BL/6) mice or mice with syngeneic day-7 to day-12 B16 melanoma metastases established in various organs. The overall biodistribution of the T-LAK cells was measured by gamma counting and their tumor localization by fluorescence microscopy. Results: At 16 h after intravenous injection, the organ distribution of ¹²⁵I-dU-labeled T-LAK cells was identical in normal and tumor-bearing animals. Fluorescence microscopy of lung tissue from animals receiving TRITC-labeled T-LAK cells revealed, however, a fivefold higher accumulation of T-LAK cells in lung metastases than in the surrounding normal lung tissue (1174 and 226 cells/mm² respectively). Some pulmonary metastases were, however, resistant to infiltration. Very few intravenously injected cells redistributed to other organs or to tumors in these, since only 60 and 30 T-LAK cells/mm² were found within metastases of the adrenal glands and the liver respectively. However, following injection of T-LAK cells via the left ventricle of the heart, a threefold increase (from 60 to 169 cells/mm²) in the number of transferred cells in metastases of the adrenal glands was observed. Moreover, following locoregional administration of T-LAK cells into the portal vein, tenfold higher numbers (from 30 to 400 cells/mm²) were found in hepatic metastases than were observed following intravenous or intracardiac injection. In the liver, a surprisingly large number of intraportally injected T-LAK cells (approx. 1300/mm²) were observed to accumulate in the perivascular spaces of the portal, but not the central veins. Even though some superficial ovarian and liver metastases were separated from the peritoneal cavity by only the peritoneal lining, no localization into these metastases was seen following intraperitoneal injection of the T-LAK cells. While treatment of tumor-bearing animals with T-LAK cells plus IL-2 reduced lung metastases by 76% as compared to treatment with IL-2 alone (P < 0.03), no significant reduction of liver metastases was seen. Conclusions: T-LAK cells are able to localize substantially into tumor metastases in various anatomical locations, but mainly following locoregional injection. This finding might have important implications for the design of future clinical protocols of adoptive immunotherapy based on T cells. Received: 29 April 1999 / Accepted: 5 August 1999     

Glycogen accumulation and phase separation drives liver tumor initiation

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Biliary excretion and distribution of 51Cr(III) and 51Cr(VI) in rats

The biliary excretion and distribution of 51Cr after intravenous administration of 51Cr(III) (61CrCl5) or 51Cr(VI) (Na252CrO4 . 4 H2O) was studied in rats. The cumulative biliary excretion of 51Cr reached 24 hrs after the injection was significantly higher after administration of 51Cr(VI) than after 51Cr(III) 3.51+/-0.7% and 0.51+/-0.05% of administered dose, respectively). This difference was especially due to a higher rate of biliary excretion of 51Cr in the first hours after 51Cr(VI) administration. The excretion of 51Cr via faeces was also higher after administration of 51Cr(VI) (7.35+/-0.45%) OF ADMINISTERED DOSE, AS AGAINST 4.23+/-0.23% after 51Cr(III). On the other hand, no significant difference in urinary excretion of 51Cr was found. Statistically significant differences were also observed in the distribution of 51Cr in the organism after administration of both valence states of the metal.     

Biodistributions of radioactive bipositive metal ions in tumor-bearing animals

Distributions of the nuclides ⁶⁵ZnCl₂, ⁸⁵SrCl₂, ⁵⁸CoCl₂ and ¹⁰³PdCl₂ in tumor-bearing animals were determined, and, in addition, the distributions of these nuclides in tumor tissues were observed. Their subcellular distribution in tumor and liver was also examined. Generally speaking, retention values of these bipositive metal ions in tumor were smaller than those of tri-, quadri- and pentavalent metal ions. In the case of ⁸⁵SrCl₂, a large amount of this nuclide was taken up by the bone and remained there for a long time. In the case of ¹⁰³PdCl₂, ^l03Pd was avidly taken up by the kidney and liver. Very little of the ¹⁰³Pd taken up into the kidney and liver was excreted. ⁶⁵Zn and ¹⁰³Pd were concentrated in the viable tumor tissue and were not seen in necrotic tumor tissue. In the case of ⁵⁸Co, lysosome played an important role in liver accumulation and played a minor role in tumor accumulation. The distribution of ⁵⁸Co in tumor and liver was fairly similar to that of ⁶⁷Ga, ¹¹¹In, ¹⁶⁹Yb, ⁴⁶Sc, ⁵¹Cr, ⁹⁵Zr, ¹⁸¹Hf, ⁹⁵Nb and ¹⁸²Ta which were reported previously. Lysosome did not play an important role in the accumulation of ⁶⁵Zn, ⁸⁵Sr and ¹⁰³Pd into tumor and liver.