Enhancement of colloid uptake by tumor cell surface electrical charge modification.

Colloidal [51Cr]chromic phosphate uptake is considerably increased by preincubation of P388 ascites leukemia cells with poly(DL-lysine). The uptake increase is in direct relationship with the concentration and the degree of polymerization of poly(DL-lysine). The probable implication of cell surface electrical charge modification in these phenomena is discussed.

Radiofrequency-induced carcinogenesis: cellular calcium homeostasis changes as a triggering factor.

The aim was to study the effects of radiofrequency (Rf) in a mice strain characterized by age-determined carcinogenesis of lymphatic tissues. Mice were treated with a 1?h/week Rf exposure for 4 months. A group submitted to sham exposure was used as control animals. The evolution of carcinogenesis was followed up to 18 months. The maximal life span of control mice was about 24 months. All dead animals were clinically and histologically examined to give an age-determined comparative quantification of the evolving carcinogenesis. A radiocalcium tracer method permitted the evaluation of Rf effects on transmembrane transport of extracellular calcium at 1 and 24 h after exposure. The determination of induced lipid peroxidation completed this second study. The findings show that Rf provoked an earlier general lymphocyte cell infiltration, formation of lymphoblastic ascites and extranodal tumours of different histological types, as well as an increased early mortality. The results suggest that in Rf-exposed mice, carcinogenesis may be induced earlier and with different pathological forms than in control animals. The modifications in cellular calcium homeostasis and the age-determined thymus involution appear to be important factors involved in this carcinogenesis process.

Ehrlich tumour cells: Ca(2+)-uptake modification by aluminium lactate.

Aluminium lactate provokes the same modification of 45Ca(2+)-uptake by Ehrlich ascites tumour cells as does ferric lactate. The increase of uptake is metal-complex concentration-dependent, and in contrast to ferric lactate, is only partially inhibited by albumin. Under the same experimental conditions, chromic lactate provoked no modification of that uptake. A plasma membrane rigidity increase provoked by coordination binding of aluminium to phospholipids is likely to be the main cause of Ca(2+)-uptake modification by aluminium lactate.

Effects of Fe(3+)-tumor cell interaction on Ca(2+)-uptake by Ehrlich ascites tumor cells.

Fe3+ ions complexed by various ligands induce an increased Ca2+ uptake by Ehrlich carcinoma ascites cells that is proportional to the thermodynamic stability constant of the complex, and the greatest increase is observed with ferric lactate. The absence of ATPase inhibition showed by this ferric complex, suggests that an increased passive diffusion of Ca2+ due to structural modifications of the cell membrane is the most probable cause of this phenomenon.

Labeling of erythrocytes with 103Ru-ruthenium red.

The preparation of 103Ru-ruthenium red and its use in the labeling of erythrocytes is described. Since in vivo and electrophoretic studies indicate that the tag is firmly bound to the cell, this technique appears to be very convenient for spleen scintigraphy and for the study of the in vivo fate of tagged cells.

Mechanisms of gallium-67 accumulation by tumors: role of cell membrane permeability.

The effects of citrate ion on in vitro and in vivo uptake of [67Ga]citrate by tumor cells have been studied. Carrier-free [67Ga]citrate seems to follow the physical diffusion of citrate ions into the cell, and the presence of carrier gallium inhibits that diffusion, reducing considerably its uptake. These results appear to support the hypothesis that increased permeability of tumor cells is the principal cause of [67Ga]citrate accumulation by tumors.

Role of iron in lymphoma-induction by ATP.

Iron complexed by ATP induces lymphomas in mouse organs other than the specific targets of the lympho-adenitis provoked by sodium ATP: lymph nodes, spleen and liver. The reduction of life spans and the production of substantial volumes of ascites, that are lacking in the case of sodium ATP, are an index of the degree of malignancy of the induced lymphomas. On the basis of the known characteristics of iron-ATP complex of cellular calcium homeostasis alteration, the mechanism of these phenomena is discussed.

Effects of complexed iron and aluminium on brain calcium.

Ferric lactate increases Ca(2+)-uptake by Ehrlich carcinoma ascites cells as well as in vitro and in vivo Ca(2+)-uptake by the liver. Iron and aluminium are increased in the substantia nigra of patients with Parkinson's disease and aluminium is suspected to be involved in the pathophysiology of Alzheimer's disease. This study was conducted to determine if there is any relationship between iron and aluminium uptake and a possible calcium influx into brain tissue. Groups of Swiss mice were injected in the tail vein with 100 microliters of 0.05 M ferric lactate plus 2 microCi45CaCl2, or 100 microliters of 0.05 M aluminium lactate plus 2 microCi45CaCl2, or 100 microliters of saline plus 2 microCi45CaCl2. Twenty-four hr later they were sacrificed by decapitation. Samples of blood and the total brain were weighed and ashed. The ashes were dissolved and the solution transferred to counting vials evaporated to dryness. A scintillation solution was added to the vials and the radioactivity was counted. To accurately assess brain uptake in each animal the value of brain specific activity was related to blood specific activity. When compared to those of control animals, these values gave the 24 hr increase of 45Ca-uptake by brain of ferric lactate or aluminium lactate-treated animals. A significant increase of 45Ca-uptake was observed for ferric lactate (136% of control value, p less than 0.005), which is more important for aluminium lactate (163% of control value, p less than 0.001). The nature of the complexed metal-brain tissue interaction is not known, several mechanisms are discussed.

ATP in iron overload-induced intracellular calcium changes.

The cellular iron uptake from low molecular weight iron complexes (ferric citrate, ferric lactate and ferric ATP complex) is concentration-dependent, and only a small part of the iron penetrates the cell as shown by deferoxamine treatment. A threshold of iron concentration in the cell must be reached for the iron complex-induced increase of cellular Ca2+-uptake. ATP seems to play a key role in an iron translocation that enhances the effects of the iron complexes. A non-specific and competitive iron-binding by proteins seems to act as a buffer system that reduces the iron overload effects. Calcium channel blockers have no effects on the iron complex-cell interaction or iron-induced Ca2+-uptake modification. An iron complex concentration-dependent inhibition of the CaATPase activity, and its consequent Ca2+-extrusion impairment appear as the likely cause of calcium overload. The relevance of these findings in iron overload-induced pathologies is discussed.

Iron chelation and tumor cell calcium homeostasis.

The effects of iron chelation on calcium homeostasis of Ehrlich carcinoma cells were studied using 59Fe-ferric lactate and 45CaCl2. Desferrioxamine action on bound iron is characterized by the presence of an insoluble fraction located deep in the cell membrane and another soluble fraction on the cell surface. The competitive binding by albumin suggests that the iron is bound by protein containing molecular structures of the cell. The modification of cellular calcium homeostasis induced by ferric lactate, which is a phenomenon inherent in cell injury, is not caused by lipid peroxidation. The role of iron-induced cellular calcium homeostasis in carcinogenesis is discussed.

Iron, intracellular calcium ion, lipid peroxidation and carcino-genesis.

The evaluation of the accumulated experimental results on the action of complexed iron on cells indicates that the provoked cell injury is rather the consequence of an inhibition of the cytosolic Ca2+ concentration regulatory system than an effect of iron-induced lipid peroxidation. The role of the consequent intracellular ionic environment change in the preneoplastic and neoplastic transformation of the cell is discussed.

Non-transferrin-bound iron and tumor cells.

The study of iron uptake from low molecular weight complexes by Ehrlich carcinoma cells shows concentration-dependence, and ATP increases the iron uptake from citrate and lactate complexes. Blood proteins can act as inhibitors, and deferoxamine chelation of cell-bound iron complex indicates that the percentage of iron penetrating the cell is about the same for a wide range of iron complex concentrations in the incubation medium (about 5% for ferric lactate). Ascorbic acid increases iron uptake and simultaneously decreases lipid peroxidation. Electrophoresis shows a very high iron transfer from ferric lactate to ATP, and to a lesser extent to ADP and AMP. In the pathological evolution of iron overload to a neoplasia, the probable involvement of an iron exchange between iron complexes from non-transferrin-bound iron of plasma and ATP is discussed.

Antitumor activity of gallium and lanthanum: role of cation-cell membrane interaction.

Using the vital dye inclusion method and the radioisotopic study of Ca2+-transport, we have investigated the involvement of the gallium and lanthanum plasma-membrane interaction in the cytotoxic and antitumor characteristics of both cations. The experimental results support the hypothesis that such an interaction is the principal cause of antitumor activity, either through structural changes of the cell membrane or through inhibition of the ATPase pumps.

Effects of gallium chloride oral administration on transplanted C3HBA mammary adenocarcinoma: Ga, Mg, Ca and Fe concentration and anatomopathological characteristics.

To determine the influence of the length of the treatment on the anatomopathological and biochemical intratumor changes induced by gallium, we treated C3H BA mammary adenocarcinoma-bearing C3H/HeJ mice with gallium chloride daily, for a period of either 21 or 42 days. In both cases the same dose of 200 mg/kg/24h was administered. An increase of collagen fibrosis in treated tumors as opposed to controls was only noted after 42 days, as well as a significant decrease of the intratumor magnesium and calcium concentrations that could be responsible for a reduction in the metabolic activities of the malignant cells. Remarkable intratumor gallium concentrations (38.4 +/- 30.3 nmol/g after 21 days of treatment; 13.4 +/- 7.3 nmol/g after 42 days where the necrosis is much more important) are obtained after this oral administration. There is no renal toxicity and a higher tumor/kidney concentration ratio is obtained than after acute parenteral administration. The effect of gallium may be different according to the mode of administration: it may be more cytotoxic after parenteral administration, while after oral administration it may act as a better metabolic regulator with a more selective tumor uptake and fewer side effects.

Iron- and aluminum-induced carcinogenesis.

Ferric and aluminum complexes with ATP have shown the induction of tumors in the site of subcutaneous injection, whereas sodium ATP has not. A concomitant but apparently independent phenomenon was a severe lymphoadenitis. The tumor calcium concentration showed an inverse relationship with the tumor growth rate. Carcinogenesis and lymphoadenitis are discussed considering well known effects of ferric and aluminum complexes with ATP on the cellular calcium homeostasis and of ATP on lymphatic tissue proliferation.

Non-specific tumor-seeking radiopharmaceuticals--report and future aspects.

A review is made of some currently held views regarding the mechanism of uptake of non-specific tumor-seeking labelled compounds, with special reference to the role of cell membranes and the transfer mechanisms across such membranes. Results with various radiopharmaceuticals used in tumor scintigraphy are discussed and some suggestions are made for possibly profitable research to be done in that area.

In vivo distribution of carrier protein/67Ga-complexes.

The uptake of 67Ga as citrate, chloride and complexed by carrier-proteins (lactoferrin and transferrin) has been studied in tumor- and inflammatory lesion-bearing rats. Different uptake patterns are shown by tumors and lesions. 67Ga-transferrin complexes are taken up to the highest extent by tumors and inflammatory lesions. The comparative distribution studies using normal animals indicate a systemic increase of 67Ga uptake by tumor- and lesion-bearing animals which might be of importance in explaining the mechanism of 67Ga accumulation. The role of ionic environment changes and radioactivity concentration by isomorphous ionic replacement is discussed.

On the role of tumor cell surface in the accumulation of radioisotopes.

The effects of electrical charge and structural modifications of the ascites tumor cell surface on the uptake of several radiocompounds have been investigated. Changes in its electrical surface charge provoke variations in the radioactivity incorporation which appear to be selective for chelated or ionic radioisotopes. The release of a part of the cell "coat" by EDTA affects profoundly the incorporation of radioisotopes in a process which seems to be related to cell membrane permeability changes. The relationships between cell surface changes and radiocompounds accumulation are discussed.

On the accumulation of 57Co by pancreas.

The in vivo distribution of various 57Co-labelled compounds has been studied. 57Co-citrate is concentrated by pancreas and when injected together with ferric citrate the pancreas uptake is increased while it decreases in liver and kidney.

57Co-hematoporphyrin accumulation by experimental tumors.

The in vivo distribution of 57Co-hematoporphyrin in adenocarcinoma BW10232-bearing mice has been studied. Tumor-bearing and normal animals exhibit similar patterns of radioactivity accumulation. Twenty-four hours after the administration of the radiocompound the ratios tumor to blood and tumor to muscle indicate a potential value of this radioactive porphyrin for the detection of some types of tumor.