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PubMed1983

Methodological aspects of microelectrode measurements in cellular spheroids.

Different types of oxygen microelectrodes have been tested in measurements on cellular spheroids. The shape of the oxygen gradients varied strongly depending on size and type of the spheroids. No significant differences in the results were obtained when different types of electrodes were applied. All measurements were made in a perfusion chamber. The shape of the gradients did not vary with time in the perfusion chamber. The reproducibility was found good in repeated measurements using the same spheroid. No mechanical or chemical disturbances were seen during the penetration of the spheroids. Changes in the medium flow rate through the chamber did not drastically change the shape of the oxygen gradients. Almost no convection could be seen at the bottom of the chamber close to the spheroids. The composition of the medium was found to be of importance. Lock's solution containing glucose was found to be satisfactory. The potential signals in the double barrel electrodes allowed an accurate determination of the position when the electrode hit the spheroid surface. The information gained from microelectrode measurements in spheroids might be valuable for the understanding of effects of new tumor treatment modalities in which hypoxic cell sensitizers or high LET radiation are utilized.

Animals↗
PubMed1986

Effects of radiation on host-tumor interactions using the multicellular tumor spheroid model.

Use of the multicellular tumor spheroid as a tumor model allows separate host or tumor treatment with ionizing radiation and examination of the effects on host-tumor immune interactions. Spheroids of EMT6/Ro, a BALB/c mammary tumor were implanted into the peritoneal cavity of syngeneic immunized mice, recovered, and dissociated into single cells. Cytolytic activity of mature spheroid associated cells and peritoneal cells was resistant to radiation doses as high as 1000 rads when irradiate directly prior to assay. Mice irradiated (200, 400, 700 rads) 24 h prior to spheroid injection had an increased number of tumor cells and decreased number of tumor infiltrating and peritoneal host cells upon spheroid recovery. This was paralleled by an increased colony forming efficiency per spheroid. Cytolytic activity of the spheroid associated cells against radiolabeled EMT6 cells was in many cases decreased with radiation although lysis was the same on a per cell basis. Cytolytic activity by peritoneal cells from these mice increased with dose as measured on a per cell basis. This activity from irradiated animals was carried out by a Thy1+ cell.

Animals↗
PubMed1976

"Axonal spheroids" in the spinal cord of normal rabbits.

Within the gray matter and the white matter of the spinal cord of apparently healthy rabbits, myelinated and unmyelinated axonal swellings, so callled "xonal spheroids", occur. Most of the spheroids contain mitochondria, dense bodies, vesicles and fragments of the tubular or smooth endoplasmic reticulum. In myelinated spheroids the process of swelling is effected by slippage of the myelin leaflets. At the periphery of the unmyelinated parts of the spheroids, synapses are regularly found. The presynpatic terminal bouton is formed by the spheroid. A few myelinated and unmyelinated spheroids are packed with fine granular material while mitochondria are lacking. The axonal spheroids may represent a physiological, perhaps agedependent phenomenon.

Aging↗
PubMed1991

Effects of 131I-labeled TNT-1 radioimmunotherapy on HT-29 human colon adenocarcinoma spheroids.

Radiolabeled murine monoclonal antibody TNT-1, directed against the nuclear histones of degenerating cells, was used to treat human colon adenocarcinoma HT-29 spheroids in vitro. The therapeutic effects of 131I-TNT-1 were investigated as a function of the radioactive dose, treatment time, and number of treatments. Efficacy of treatment was assessed by TNT-1 antibody uptake, spheroid growth delay, and morphological examination using light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). From these studies, it was determined that the therapeutic effect increased with the number of doses and the duration of treatment. Spheroids treated for 24 h showed approximately two to four times more cell death than those with a 2-h treatment. As previously shown in animal models, additional treatment with radiolabeled TNT-1 produced an expanding number of TNT-1 targets, and subsequent treatments were more effective as shown by antibody uptake studies. Microscopic examinations demonstrated that morphological changes consistent with spheroid destruction correlated well with antibody uptake data and increased gradually with dose, treatment time, and frequency of treatments. At the ultrastructural level, destruction of cells in the treated spheroids included the formation of porous cell membranes, crater-like holes (SEM), blebbing, and dissolution of cytoplasmic organelles (TEM). With continued culture, the injured spheroids were found to disaggregate after intensive 131I-TNT-1 therapy (e.g. 50 microCi/ml or 100 microCi/ml with two or three 24-h treatments). These findings suggest that tumor spheroids can be used as an in vitro model to evaluate monoclonal antibody therapy using TNT-1 and other candidate mAbs directed against intracellular antigens exposed in degenerating cells of tumors.

Adenocarcinoma↗
PubMed1983

Penetration of substances into tumor tissue: a methodological study with microelectrodes and cellular spheroids.

A new method was tested for studies of penetration of substances into tumorlike tissue. The penetration of the ions K+, Cl-, and Ca2+ through several layers of tumor cells was demonstrated by using double barrelled, ion sensitive microelectrodes with extra thin tip diameters. Spheroids consisting of human glioma, U-118 MG, and human thyroid cancer, HTh-7, cells were used as models of tumor tissue. A microelectrode was inserted into the center of a spheroid. Thereafter, the concentration of the test substance was increased in the surrounding medium. The change in concentration inside the spheroid was recorded and the penetration pattern evaluated. All three types of tested ions penetrated easily through the spheroids. The K+ ions penetrated most efficiently, and the Ca2+ ions showed the slowest penetration. The Ca2+ ions penetrated somewhat more slowly in the U-118 MG spheroids (which had rather small extracellular spaces) than in the HTh-7 spheroids (which had larger extracellular spaces). Ion sensitive electrodes, which are easily available, were used in this study only to demonstrate the principle. We hope that the method described can be used for penetration studies of various substances. For example, all substances that can be detected by enzyme microelectrodes could be studied. The main advantage of the method is that the complete penetration pattern can be studied as a function of time in individual spheroids. Previously described methods require histological procedures for each analyzed penetration time.

Biological Transport↗
PubMed1995

Extended liver-specific functions of porcine hepatocyte spheroids entrapped in collagen gel.

The potential use of porcine hepatocytes in a bioartificial liver device requires large quantities of viable and highly active cells. To facilitate the scaling up of the system, liver specific activities of hepatocytes should be maximized. One way of enhancing the specific activities is to cultivate hepatocytes as multicellular spheroids. Freshly isolated porcine hepatocytes form spheroids when cultivated in suspended cultures. These spheroids exhibit higher activities for a number of liver specific functions compared to hepatocytes cultivated as monolayers. However, these activities decreased in a few days in culture. Entrappment of spheroids in collagen gel sustained their metabolic activities at a stable level over 21 days. Production of albumin and urea by spheroid hepatocytes entrapped in collagen gels were 2 to 3 times higher than those by freshly isolated single cells. P-450 activity was demonstrated by metabolism of lidocaine to its main metabolite, monoethylglycinexylidide. Phase II drug metabolism was demonstrated by glucuronidation of 4-methylumbelliferone. This work shows that porcine hepatocyte spheroids entrapped in collagen maintain differentiated functions for an extended time period. Such hepatocyte spheroid entrappment system may facilitate the development of a bioartificial liver support device.

Albumins↗
PubMed1990

Slow penetration of anthracyclines into spheroids and tumors: a therapeutic advantage?

Despite clear evidence that the effective penetration of the anthracycline antibiotics into experimental tumors or multicell spheroids is poor, these drugs exhibit clinical activity against a variety of solid tumors. In an attempt to understand this apparent contradiction, we used the Chinese hamster V79 spheroid system and flow cytometry techniques for intra-spheroid pharmacological studies of doxorubicin and daunomycin. Our results indicate that the slow delivery of the anthracyclines to the inner cells of spheroids is due to the rapid binding of the drug by cells in the outer layers. After exposure, the anthracyclines are retained much more effectively when cells remain in intact spheroids than when the spheroids have been dispersed, resulting in considerably more cytotoxicity in situ. This result indicates a need for considerable caution in attempting to predict the anti-tumor efficacy of drugs by using either conventional cell-culture systems, spheroids that have been disaggregated immediately post-exposure, or excision assays of tumors from experimental animals. Furthermore, our results suggest the need for a critical evaluation of the significance of the multidrug resistance (MDR) phenotype for cells surrounded by other drug-containing cells as opposed to single cells in drug-free culture medium.

Animals↗
PubMed1994

Effect of purine synthesis inhibition on WiDr spheroids in vitro or on WiDr or colon 38 tumors in vivo. Complete growth inhibition but not regression.

Clinical responses for anticancer agents are based upon tumor regression. We have investigated the potential of glycineamide ribonucleotide transformylase (GAR TFase) inhibitors to produce regressions in multiple preclinical models of colon carcinoma. The growth of multicellular tumor spheroids of WiDr human colon carcinoma was inhibited by the GAR TFase inhibitors 5-deazaacyclotetrahydrofolate (5-DACTHF), its 2'-fluoro, 3'-fluoro, 10-deaza, and 10-thia analogs as well as 5,10-dideazatetrahydrofolate, but none of the compounds caused spheroid regressions. By contrast, complete spheroid disruption was observed with exposure to etoposide, m-AMSA (amsacrine), piritrexim, or 2-desamino-2-methyl-10-propargyl-5,8-dideazafolate (DMPDDF). Light microscopy of the spheroids treated with either 5-DACTHF or DMPDDF suggested that the reason for the difference is extensive cell kill throughout the spheroid in the presence of DMPDDF compared with little or no kill, over that found in controls, with 5-DACTHF. Treatment of spheroids with 5-DACTHF in the presence of 1 microM hypoxanthine resulted in no significant reversal of growth inhibition; 50% reversal required 10 microM hypoxanthine. The spheroid studies were extended to in vivo studies examining the effects of 5-DACTHF on established WiDr and colon 38 tumors. The results showed that, in contrast to melphalan, which produced cures and tumor regressions, 5-DACTHF produced reversible growth inhibition with no significant regression of tumors. The results predict that clinical response, typically measured by tumor regression, may be rare following single agent therapy with inhibitors of de novo purine biosynthesis.

Acyltransferases↗
PubMed1990

NMR studies of the lipid metabolism of T47D human breast cancer spheroids.

The in vivo 31P NMR spectrum of T47D human breast cancer cells grown as spheroids shows changes in the phosphomonoester lipid precursors as a function of spheroid size. The ratio of phosphorylethanolamine (PE) to phosphorylcholine (PC) was 1.0 +/- 0.3 for 3-day-old, 150 microns spheroids. This ratio increased to 2.4 +/- 0.4 for spheroids 7 days and older and which were at least 300 microns in diameter. To investigate the phosphatidylethanolamine to phosphatidylcholine (PdylE/PdylC) ratio in the membranes, chloroform/methanol extracts of spheroids were performed. The 31P spectrum of these extracts showed no change with spheroid size, namely the PdylE/PdylC ratio was 0.5 +/- 0.06 for spheroids of all ages suggesting that membrane composition is strongly regulated at the precursor level.

Breast Neoplasms↗
PubMed1983

The relative resistance of non-cycling cells in 9L multicellular spheroids to spirohydantoin mustard.

Surviving fractions of 9L spheroid cells treated with 1.5, 3.0 and 6.0 micrograms/ml of spirohydantoin mustard (SHM) decreased when assayed 6 hr after treatment but increased thereafter. Flow cytometric analysis showed that exponentially growing 9L monolayer cells treated with SHM accumulated at the G2/M border within 24 hr. Cells dissociated from spheroids treated with 3 and 6.0 micrograms/ml of SHM accumulated at the G2/M border during the first 24 hr after treatment and remained there for the next 12 hr. However, 50% of the cells remained at the 2C DNA peak. Spheroid cells with 2C DNA content 24 hr after treatment were assumed to be non-cycling cells at the time of treatment, and cells that accumulated at the G2/M peak appeared to be cycling cells at the time of treatment; approximately 50% of cells in untreated 9L spheroids are in the noncycling pool. G1 and/or early S phase 9L cells in exponential growth elutriated immediately after treatment with SHM had significantly lower (P greater than 0.001) plating efficiencies than 9L cells in S and G2/M phases. When spheroids were dissociated, elutriated and plated for colony-forming efficiency 24 hr after treatment with 3 micrograms/ml of SHM, fractions enriched in 2C DNA content had significantly higher (P greater than 0.001) plating efficiencies than elutriated cells enriched in 4C DNA. These results indicate that SHM is less effective against non-cycling 9L spheroid cells with 2C DNA content than against cycling 9L spheroids cells.

Animals↗
PubMed1984

Binding of misonidazole to V79 spheroids and fragments of Dunning rat prostatic and human colon carcinomas in vitro: diffusion of oxygen and reactive metabolites.

Differences were noted previously in the binding of 14C-Misonidazole (MISO) to V79 and EMT6 spheroids when incubated at low oxygen levels. While binding to the viable cells in EMT6 spheroids was uniform, in V79 spheroids the binding rate increased gradually with distance from the spheroid surface. Further data reported here indicate that the Km for the inhibition of binding by oxygen is lower in V79 than EMT6 spheroids, so that part of the non-uniformity of binding to V79 spheroids can be explained by diffusion of small amounts of oxygen through the entire rim of viable cells. Diffusion of reactive metabolites of MISO out of the spheroid previously was considered an unlikely explanation. Further evidence to support this interpretation is presented here. Patterns of binding of 3H-MISO to Dunning and human colon carcinomas are presented which are consistent with the interpretation that most of the reactive metabolites are confined to the cell in which they are produced. This conclusion is based on a substantial difference in the rate of binding to adjacent stromal and tumor elements.

Animals↗
PubMed1985

Influence of the oxygen pressure in the culture medium on the oxygenation of different types of multicellular spheroids.

Six different types of spheroids of both human and rodent origin were cultured, using the liquid-overlay technique. Oxygen gradients were measured with micro-electrodes, when the spheroids were attached to thin cover-glasses. The gradients were measured from the upper surface towards the center of the spheroids. Stable and reproducible gradients were obtained. Large variations were seen in the steepness of the gradients, depending both on the type and on the size of the spheroids. An interesting phenomenon was discovered. When some types of spheroids were cultured in a medium with a low oxygen pressure (medium equilibrated with gas containing 4-5% O2), the gradients continuously changed and became flatter. Detailed studies showed that most of the changes occurred within 2 days after the transfer to the low oxygen pressure. After 2 days, no further dramatic changes took place. This phenomenon was seen in two types of human glioma (U-118 MG and U-178 MG) and two types of embryonic, hamster lung-cell (V-79-379A and CHEL) spheroids. In the cases of human-osteosarcoma (U-393 OS) and human thyroid-cancer (HTh7) spheroids, no such changes could be seen. The low oxygen tension in the culture medium was chosen to mimic the environmental conditions in solid tumors.

Animals↗
PubMed2005

Growth inhibition of estrogen receptor-positive and aromatase-positive human breast cancer cells in monolayer and spheroid cultures by letrozole, anastrozole, and tamoxifen.

Two third-generation aromatase inhibitors, letrozole and anastrozole, and the antiestrogen tamoxifen, were compared for growth-inhibiting activity in two estrogen receptor (ER)-positive aromatase-overexpressing human breast cancer cell lines, MCF-7aro and T-47Daro. Inhibition of hormone (1 nM testosterone)-stimulated proliferation was evaluated in both monolayer cultures and in three-dimensional spheroid cultures. Letrozole and anastrozole were also compared for effectiveness of aromatase inhibition, and relative affinity for aromatase, under both monolayer and spheroid growth conditions. Letrozole was an effective inhibitor of MCF-7aro monolayer cell proliferation, with an estimated 50% inhibitory concentration (IC50) of 50-100 nM, whereas an IC50 was not reached with anastrozole at any concentration tested (100-500 nM). An IC50 of tamoxifen was 1000 nM. Proliferation of T-47Daro monolayer cells was more sensitive to inhibition by all three agents; as with MCF-7aro cells, letrozole was the most effective inhibitor. MCF-7aro spheroids were slightly less sensitive than monolayer cells proliferation-inhibiting effects of letrozole (IC50 about 200 nM), and there was no significant inhibition with 100-200 nM anastrozole or 200-1000 nM tamoxifen. Letrozole and anastrozole significantly inhibited T-47Daro spheroid cell proliferation, at 15-25 and 50 nM, respectively, consistent with the greater sensitivity of T-47Daro monolayer cells to inhibition of proliferation by these agents. Tamoxifen failed to significantly inhibit T-47Daro spheroid cell proliferation over a 100-500 nM concentration range. Determination of aromatase inhibition in monolayers of both cell lines by a direct-access microsomal assay and an intact-cell assay revealed that letrozole was more active than anastrozole in monolayers of both cell lines and in both assays. In MCF-7aro spheroids following cell lysis, only letrozole significantly inhibited aromatase activity, supporting the conclusion that letrozole binds stronger to aromatase than anastrozole does. Our results demonstrate that MCF-7aro and T-47Daro spheroids could be a suitable model for evaluation of growth-inhibitory effects of agents used in hormonal therapy of breast cancer.

Anastrozole↗
PubMed2003

Plasminogen activator/plasmin system regulates formation of the hepatocyte spheroids.

The isolated rat hepatocytes inoculated onto the surface of positively charged culture dishes are anchored initially and then begin to migrate and aggregate gradually to form multicellular spheroids detached from the dish. We studied the roles of fibrinolytic factors in the spheroid formation. The fibrinolytic factors, tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA), were increased in the course of spheroid formation. Then, we introduced fibrinolytic inhibitors into the spheroid cultures to determine functions of fibrinolytic factors. Plasmin inhibitor inhibited markedly the spheroid formation. Interestingly, the anti-plasmin antibody showed different effect depending on the timing of its administration. In summary, we demonstrated for the first time that induction of PAs and ensuing plasmin generation on the cell surface play important roles in hepatocyte spheroid formation, and that plasmin is involved in the different processes such as cell migration and cell detachment in the formation of hepatocyte spheroid.

Animals↗
PubMed2002

Evaluation of 3-nitrotyrosine as a marker for 3-nitropropionic acid-induced oxidative stress in Lewis and Wistar rats and strain-specific whole brain spheroid cultures.

The present study investigated whether 3-nitrotyrosine is an early marker for neurodegenerative processes involving oxidative stress. We characterized the 3-nitrotyrosine formation after 3-nitropropionic acid (3-NP) exposure in the whole brain spheroid culture model and in a rat model, using Lewis and Wistar rats. Increased 3-nitrotyrosine concentration in spheroid cultures from Lewis rats was observed at lower dose of and shorter exposure time to 3-NP as compared to alterations in glial fibrillary acidic protein concentration, decrease in glutamine synthetase activity or cell loss. Five days of exposure to 3-NP (5 mM) resulted in decreased staining of GABAergic processes, while neuronal nitric oxide synthase staining was preserved. In addition, staining of EAAC1, anti-2',3'-cyclic nucleotide 3'-phosphohydrolase and ED1 was diminished after treatment of spheroid cultures with 3-nitropropionic acid (5 mM), while isolectin B4 staining was increased. Dithiothreitol and vitamin E inhibited the increased formation of 3-nitrotyrosine. Interestingly, N(G)-nitro-L-arginine methyl ester increased the 3-nitrotyrosine formation. No increased 3-nitrotyrosine concentration was shown after exposure to 3-nitropropionic acid during 5 days in spheroid cultures obtained from Wistar rats. In the striatum of 3-NP-exposed Lewis and Wistar rats, no change in 3-nitrotyrosine concentration was observed, whereas only in Wistar rats the glial fibrillary acidic protein concentration was increased in addition to activation of microglial cells. It is concluded that 3-nitrotyrosine was a more sensitive marker for oxidative stress-induced neurodegeneration than glial fibrillary acidic protein and glutamine synthase in spheroid cell cultures of Lewis rats. Finally, the similarities between the 3-NP spheroid model and the vivo model indicate that the spheroid cultures provide a good alternative for chronic exposure of animals to neurotoxins.

Animals↗
PubMed1973

A comparison of the unfolding and dissociation of the large ribosome subunits from Rhodopseudomonas spheroides N.C.I.B. 8253 and Escherichia coli M.R.E. 600.

1. The behaviour of the large ribosomal subunit from Rhodopseudomonas spheroides (45S) has been compared with the 50S ribosome from Escherichia coli M.R.E. 600 (and E. coli M.R.E. 162) during unfolding by removal of Mg(2+) and detachment of ribosomal proteins by high univalent cation concentrations. The extent to which these processes are reversible with these ribosomes has also been examined. 2. The R. spheroides 45S ribosome unfolds relatively slowly but then gives rise directly to two ribonucleoprotein particles (16.6S and 13.7S); the former contains the intact primary structure of the 16.25S rRNA species and the latter the 15.00S rRNA species of the original ribosome. No detectable protein loss occurs during unfolding. The E. coli ribosome unfolds via a series of discrete intermediates to a single, unfolded ribonucleoprotein unit (19.1S) containing the 23S rRNA and all the protein of the original ribosome. 3. The two unfolded R. spheroides ribonucleoproteins did not recombine when the original conditions were restored but each simply assumed a more compact configuration. Similar treatments reversed the unfolding of the E. coli 50S ribosomes; replacement of Mg(2+) caused the refolding of the initial products of unfolding and in the presence of Ni(2+) the completely unfolded species (19.1S) again sedimented at the same rate as the original ribosomes (44S). 4. Ribosomal proteins (25%) were dissociated from R. spheroides 45S ribosomes by dialysis against a solution with a Na(+)/Mg(2+) ratio of 250:1. During this process two core particles were formed (21.2S and 14.2S) and the primary structures of the two original rRNA species were conserved. This dissociation was not reversed. With E. coli 50S approximately 15% of the original ribosomal protein was dissociated, a single 37.6S core particle was formed, the 23S rRNA remained intact and the ribosomal proteins would reassociate with the core particle to give a 50S ribosome. 5. The ribonuclease activities in R. spheroides 45S and E. coli M.R.E. 600 and E. coli M.R.E. 162 50S ribosomes are compared. 6. The observations concerning unfolding and dissociation are consistent with previous reports showing the unusual rRNA complement of the mature R. spheroides 45S ribosome and show the dependence of these events upon the rRNA and the importance of protein-protein interactions in the structure of the R. spheroides ribosome.

Centrifugation, Density Gradient↗
PubMed1990

HPLC and flow cytometric analyses of uptake of adriamycin and menogaril by monolayers and multicell spheroids.

We have used both HPLC and flow cytometry to measure and compare the uptake of two anthracyclines, menogaril (MEN) and Adriamycin (ADR), in V79 Chinese hamster lung fibroblasts grown as monolayers and as 650 microns multicell spheroids. In order to compare intracellular drug accumulation in spheroid cells measured by the two methods, we converted mean channel fluorescence of the flow cytometer to drug uptake expressed as ng/10(6) cells by using a standard curve. The standard curve related the flow cytometric mean channel fluorescence, of monolayer cells exposed to either drug, to the intracellular drug accumulation determined by HPLC. This standard curve was then used to convert the mean channel fluorescence of cells from drug-exposed spheroids to ng/10(6) cells. Our results show that equal intracellular drug accumulation (determined by HPLC) in spheroids and monolayers does not result in equal cellular fluorescence emission (determined by flow cytometry) by these 2 cell populations. For example, monolayer cells with an intracellular MEN accumulation of 650 ng/10(6) cells, emit 40 units of fluorescence as measured by flow cytometry. However, spheroid cells with the same intracellular accumulation emit about 80 units of fluorescence. This results in the intracellular MEN uptake in spheroids measured by flow cytometry being as much as 2- to 3-fold higher than that measured by HPLC. Intracellular ADR accumulation measured by flow cytometry was also higher than that obtained by HPLC. In spite of the quantitative difference between the two methods, qualitatively both methods gave similar results. Thus, both techniques showed that at equal drug concentration in medium drug uptake in monolayers was much greater than in spheroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

A model for the growth of multicellular spheroids.

Based on biological observations and the basic physical properties of tri-dimensional structures, a mathematical expression is derived to relate the growth rate of multicellular spheroids to some easily measurable parameters. This model involves properties both of the individual cells and of the spheroid structure, such as the cell doubling time in monolayer, the rate of cell shedding from the spheroid and the depth of the external rim of cycling cells. The derived growth equation predicts a linear expansion of the spheroid diameter with time. The calculated growth rate for a number of spheroid cell types is in good agreement with experimental data. The model provides a simple and practical view of growth control in spheroids, and is further adapted to include parameters presumably responsible for the growth saturation in large spheroids.

Animals↗