Ehrlich Ascites Tumor Growth Research Articles

Effects of creatine and β-guanidinopropionic acid on the growth of Ehrlich ascites tumor cells: i.p. injection and culture study

Growth of Ehrlich ascites tumor (EAT) cells in the abdominal space of mice or in cell culture was studied in response to i.p. injection or addition, respectively, of creatine or creatine analogue β-guanidinopropionic acid (β-GPA). The increase in body weight of the mice due to cancer growth was less in the β-GPA-injected than in the creatine- or sham-injected group. The volume of abdominal ascites and total cell counts at 11th day after implantation of EAT cells was significantly less in the β-GPA than in the other groups. The proliferation rate of EAT cells in the β-GPA group was 27% and 35% of the creatine- and sham-injected groups, respectively. Supplementation of creatine tended to enhance the growth of EAT cells. The creatine concentration in ascites fluid was approximately 4-times greater than in blood plasma of sham-injected control mice. But the creatine content in EAT cells was significantly reduced to approximately 50% in response to β-GPA injection. Cell culture without creatine caused a significant decrease in viability. The viability was improved, however, by addition of either creatine or serum into the medium. By contrast, it was not significantly increased by addition of serum alone which caused only a minor elevation of the creatine level (23 μM). It is suggested that EAT cell growth is inhibited by lowering the availability of creatine in association with some unknown factors in serum or ascites fluid.

Over-expression of the small heat-shock protein, hsp25, inhibits growth of Ehrlich ascites tumor cells

hsp25 is a small, growth-related, mammalian stress protein which is highly accummulated in the stationary phase or Ehrlich ascites tumor in vivo. Ehrlich ascites cells cultivated in vitro under conditions of continuous exponential growth express hsp25 only at a low level. These cells were stably transfected with an eukaryotic expression vector carrying the coding sequence of the small heat-shock protein, hsp25, under control of the murine metallothionein promoter. The resulting cell lines (EAT 116 and EAT 118) exhibit constitutive over-expression of the small heat-shock protein. hsp25, which can be further increased by induction with cadmium. Both cell lines show increased thermoresistance. The in vitro proliferation rate of the transfected cell lines EAT 116 and EAT 118 is significantly decreased depending on the degree of cadmium-regulated over-expression of hsp25. Furthermore, a significant delay in Ehrlich ascites tumor growth in mice using the hsp25 over-expressing cells for primary inoculation could be demonstrated.

Reconstituted basement membrane (Matrigel) promotes the survival and influences the growth of murine tumors.

The effects of reconstituted basement membrane (Matrigel) on in vivo survival and growth of several murine tumors were studied. Survival of tumor cells was enhanced in all experiments which resulted in increased incidence and/or in increased tumor mass. While basement membrane enhanced the in vivo growth of B16F6 melanoma cells, survival of these mice was prolonged. Basement membrane increased the incidence but reduced the growth of Ehrlich ascites tumor. Walker-256 hypercalcemic breast carcinosarcoma growth was enhanced and glandular-like structures were observed when grown on Matrigel. The results indicate that the enhanced survival of tumor cells in the presence of basement membrane is not unequivocally linked with increased malignancy.

Changes in the populations of null, NK1.1 +, and Thy1 lo lymphocytes in the bone marrow of tumor-bearing mice: Effect of indomethacin treatment

Mouse bone marrow produces many “null” lymphocytes which lack B and T lineage markers (B220 −Thyl −). A subset of these cells expresses the natural killer (NK) cell marker, NK1.1. In addition, some rapidly renewed bone marrow lymphocytes express low intensities of Thy1 (Thy1 lo). In view of their possible implication in tumor-host interactions these various cell populations have now been examined in mice injected with either the nonmetastatic Ehrlich ascites (EA) tumor or the Lewis lung carcinoma (LLc), a highly metastatic solid tumor. In each case, the number of null lymphocytes, as defined by a lack of radioautographic labeling of either B220 glycoprotein or Thyl, increased markedly in both the bone marrow and spleen. Treatment with the prostaglandin inhibitor, indomethacin, enhanced the increase in null cells in the bone marrow and spleen of LLc-bearing mice. The number of null small lymphocytes expressing NK1.1, as detected by combined radioautographic and immunoperoxidase techniques, increased almost 30-fold in LLc-bearing mice. The number of Thy1 lo small lymphocytes increased in parallel with null cells during EA tumor growth. The findings accord with the hypothesis that the null lymphocyte population produced in mouse bone marrow includes newly formed NK lineage cells which sequentially express NK1.1 and Thy1 lo. The present work demonstrates that the populations of null, NK.1.1 +, and Thy1 lo lymphocytes in mouse bone marrow expand rapidly during the early growth of transplanted tumors, the initial increase in null lymphocytes apparently being curtailed by prostaglandin production. The results suggest that the production of null lymphocytes in mouse bone marrow is responsive to tumor development, possibly providing cells to be involved in tumor-host interactions.

Changes in plasma gangliosides in relation to tumor growth modified by vitamin A

Treatment of Swiss male mice with vitamin A at a dose of 100 IU/mouse could inhibit the growth of Ehrlich ascites tumor in these mice almost by 50%, whereas a dose of 250 IU/mouse enhanced the growth of same tumor by 60%. The inhibitory and enhancing effects of vitamin A on tumor growth were reflected in the change in concentration of gangliosides of plasma. However, changes were quite different in those two cases. Out of six gangliosides detected in the plasma of tumor-bearing mice only three were observed to be related to the tumor growth regulatory effect of vitamin A.

Effect of Lactobacillus Acidophilus on Growth of Ehrlich Ascites Tumor in Swiss Mice

The role of Lactobacillus acidophilus LA 15 in reducing the proliferation of Ehrlich ascites tumor (EAT) was studied in Swiss male mice, over a period of 8 days. EAT cells were implanted intraperitoneally into mice on day 1 and the mice were subsequently treated intraperitoneally with whole cells of L. acidophilus. The mice were sacrificed on the eighth day to determine the effect of L. acidophilus on the proliferation of EAT cell growth. Control mice were injected with an equal volume of phosphate-buffered saline. There was a significant reduction in the proliferation of EAT cell due to L. acidophilus treatment. Three strains of L. acidophilus were efficacious in reducing the proliferation of EAT cell growth but the differences among L. acidophilus strains were not significant. Cell wall solids, but not non-cell wall solids reduced proliferation of EAT cells. Although L. acidophilus whole cells reduced proliferation of EAT cells, they were not as efficacious in decreasing proliferation of EAT cells in hy...

Effect of plasma gangliosides on the growth of ehrlich ascites tumor

Total plasma gangliosides of Ehrlich ascites tumor-bearing mice enhanced tumor growth when adoptively transferred with the same tumor cells in mice. However, individual gangliosides acted differently. Out of 6 gangliosides separated from plasma, 2 components enhanced tumor growth, whereas the remaining 4 inhibited tumor growth. Neither of the 2 enhancing components in various combinations with the 4 inhibitory components could restore the enhancing effect. The enhancing effect was restored only when both the enhancing components were mixed with the remaining 4 ganglioside components, i.e., with full/complete reconstitution.

Inhibition of Ehrlich ascites tumor in vivo by PAF-antagonists

Several lines of evidence support that PAF modulates the inflammatory and immune responses, and that tumors may inhibit both these processes. In the present study we analysed the effect of PAF antagonists on the growth of Ehrlich Ascites Tumor (EAT) in vivo. Mice were inoculated intraperitoneally with 1 × 10 3 EAT cells and the tumor growth evaluated by counting the number of peritoneal cells, 1, 6 and 10 days after tumor implantation. BN 52021 was administered intraperitoneally, intravenously or subcutaneously once or twice a day, at 1.0, 2.5, 5.0 and 20.0 mg/kg. Control animals received 0.1 ml of the vehicle in the same schedule. It was found that i.p. and i.v. administration of BN 52021 (5 mg/kg, twice a day) significantly inhibited EAT growth (80.8% and 56.0% respectively). Other routes and doses were less effective. Another PAF antagonist, SRI 63441 (5 mg/kg, i.p., twice a day) also inhibited EAT growth (80.4%). The BN 52021 added to EAT cells in culture, at concentration of 10 −3 and 10 −4 M, did not affect the viability and proliferation of tumors cells. In an attempt to understand the mechanism of this inhibition, we analyzed the peritoneal macrophages for spreading ability and H 2O 2 release. It was found that 24 h after tumor implantation there was an increase in the spreading ability of peritoneal macrophages (75%) and that, as the tumor grew, the spreading index fell to control levels (<10%). In the groups treated with BN 52021 (5 mg/kg/twice a day) the spreading remained elevated (50–60%) at all the times examined. Release of H 2O 2, measured by horseradish peroxidase-phenol red oxidation, was below detectable levels throughout tumor growth. Treatment with BN 52021 as above, significantly stimulated the release of H 2O 2, 6 and 10 days after tumor implantation (0.4 to 0.6 nmol/10 5 cells). The data presented show that PAF antagonists inhibit EAT growth in vivo and that this inhibition is concomitant with activation of peritoneal macrophages. These results suggest that macrophages can critically influence tumor growth and that PAF or PAF-like substances may modulate macrophages-tumor interactions.

Suppression of Ehrlich Ascites Tumors in Mice by Minute Virus of Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;

As a model system to study parvoviral oncosuppression, Ehrlich ascites (EA) cells were injected into the peritoneal cavities of ICR mice, and the effect of im injection of minute virus of mice (MVM) on EA tumor growth was examined. Coinjection with MVM resulted in a dramatic inhibition of EA tumor formation. Tumor suppression required viable, infectious virus. Mice that had survived one EA-MVM coinjection acquired long-term resistance to additional injections of EA cells.

L-histidine inhibits the growth of Ehrlich ascites tumour.

The in vitro studies on the growth of cultured Ehrlich ascites tumour cells showed similar results as the in vivo studies reported previously. The growth of tumour cells was inhibited when cultured in 0.02 or 0.03 M L-histidine. At these concentrations, L-glycine shows no significant effect.

Suppression of Ehrlich ascites tumor growth in mice by starvation and streptozotocin-induced diabetes

Starvation-induced hypoglycaemia and streptozotocin-induced diabetes suppressed the growth of Ehrlich ascites tumor in mice. The suppression of tumor growth by diabetes was alleviated by administration of insulin. The number of glucose carriers on tumour cells was found to be reduced in diabetes and partial resumption of glucose carriers was observed in tumour cells of diabetes after insulin administration. Insulin had no direct effect on tumour growth in vivo and did not affect the number of glucose carriers on tumour cells in vitro. The physiological significance of these observations is discussed.

Effect of tumour necrosis factor on growth of Ehrlich ascites tumour cells in vitro and in vivo

Tumour necrosis factor (TNF) suppressed the growth of Ehrlich ascites tumour (EAT) cells in vitro and in vivo. Exposure of EAT cells to TNF for as little as 4 h totally abolished the transplantability of the tumour. At the same time, the rate of glucose uptake and extent of leucine incorporation were significantly reduced. Prolonged treatment with TNF resulted in extensive cell lysis, as determined by trypan blue exclusion and by release of radioactivity from [ 3H]thymidine-labelled EAT cells. The significance of these observations are discussed.

Inhibition by N-(Phosphonacetyl)- l-aspartate of Ehrlich ascites tumour growth and glucose transport

N-(Phosphonacetyl)- l-aspartate (PALA) suppressed the growth of Ehrlich ascites tumour cells in vivo in a dose-dependent manner. Simultaneously as the growth rate decreased, the cellular uptake of glucose and the density of a class of glucose-reversible binding sites for cytochalasin B on the cell surface were also found to be reduced. There is a highly significant correlation between the magnitude of changes in the number of cytochalasin B binding sites and the magnitude of changes in glucose uptake. The physiological significance of these observations are discussed.

Synthesis and Antitumor Testing of 3-Methenylthiochroman-4-one-1,1-dioxide

Treatment of thiochroman-4-one-1,1-dioxide (II) with paraformaldehyde and dimethylamine hydrochloride in isopropyl alcohol at reflux afforded directly in 89% yield the dimeric dihydropyran (IV), corresponding to the dimerization of the target compound 3-methenyl-thiochroman-4-one-1,1-dioxide (III). Neither the monomer III nor the expected Mannich base, 3-dimethylaminomethylthiochroman-4-one-1,1-dioxide, were isolated under conditions of the reaction. The monomer III could be prepared in 55% yield by sublimation of the dimer IV at 230-250°; however, redimerization slowly occurred at room temperature.The dimer IV was also prepared by the use of paraformaldehyde and N-methylanilinium trifluoroacetate. The monomer III was found to be marginally active at 10 mg/kg/day versus Ehrlich ascites tumor growth in mice.

ChemInform Abstract: SYNTHESIS AND ANTITUMOR ACTIVITY OF A SERIES OF SULFONE ANALOGS OF 1,4‐NAPHTHOQUINONE

AbstractAusgehend vom Thiochromanon (Ia) wird über das Thiochromondioxid (IIIb) die Chlormethylverbindung (IV) hergestellt, die zu den Substitutionsprodukten (VI)‐(XI) umgesetzt wird.

Synthesis and antitumor activity of a series of sulfone analogues of 1,4-naphthoquinone.

A series of novel substituted thiochromones and thiochroman-4-ones was synthesized. Compounds were designed as analogues of naphthoquinone and as potential "bioreductive alkylating agents" and were tested for antitumor activity. The lead compound, 3-(chloromethyl)thiochromone 1,1-dioxide (4), inhibited Ehrlich ascites tumor growth by 100% in CF1 male mice at 10 (mg/kg)/day ip. Similarly, 18 of the 29 related compounds demonstrated good activity in this tumor screen. Few definitive structure-activity correlations were evident regarding the nature of the 3-substituent. However, the 2,3 double bond and a sulfone or sulfoxide were required for activity. Four of the compounds synthesized showed marginal but significant activity against P-388 lymphocytic leukemia.

The effect of Ehrlich ascites tumour growth on lactate dehydrogenase activities in tissues and physiological fluids of tumour bearing mice

1. 1. Tumour growth kinetics and the activity of lactate dehydrogenase (LDH) in body fluids and host tissues were studied during the Ehrlich ascites tumour growth. The rate of tumour cell death was determined by measuring the loss of 125I from mice bearing [5- 125I]iodo-2′-deoxyuridine labelled tumour cells. 2. 2. The activity of LDH in serum increased progressively with increasing tumour mass during the first period of tumour growth, whereas that of cell free ascites fluid exhibited a peak level during early plateau phase growth. The analysis of LDH activity in cell free ascites fluid revealed that the increased LDH activity could only partly be attributed to a release from dead tumour cells. 3. 3. A marked increase in host liver LDH activity was observed. In addition, the growing tumour induced an increase in RNA synthesis activity and Kupffer cell proliferation in the liver. The LDH activity in skeletal muscle decreased significantly with increasing tumour mass. 4. 4. The observations show that the growing tumour exerts a marked effect on the metabolic activity of host tissues. It is suggested that an altered metabolism affects the cell membrane integrity of certain host tissues and causes a leakage of LDH molecules, which contributes to the increased extracellular LDH activity of tumour bearing animals.

Immune mechanisms in Ehrlich ascites tumor growth in mice

Normal mice immunized with irradiated Ehrlich ascites tumor (EAT) cells rejected EAT challenge given 2 weeks later but T-cell-deficient [thymectomized lethally irradiated, and bone-marrow-reconstituted (TIR)] mice succumbed. However, when TIR mice were injected i.v. with thymus, lymph node, or spleen cells from normal syngeneic donors immediately following i.p. injection of irradiated EAT cells, they rejected the subsequent tumor challenge. This induction of immunity in TIR mice was shown to be T-cell dependent. Spleen cells from EAT-bearing mice given immediately after irradiated tumor cells were also able to promote rejection of EAT challenge in TIR mice. Spleen cells from EAT-immune mice inhibited EAT growth when admixed with tumor cells prior to i.p. injection into normal recipients, but had no effect on progressive tumor growth when given i.v. immediately after i.p. tumor injection. Immune serum inhibited i.p. EAT growth when given either i.p. or i.v. Whereas inhibition of EAT growth by admixed spleen cells was shown to be T-cell dependent, the activity of the immune serum appeared to be T-cell independent. The data indicate that T lymphocytes are required only in the induction phase of the immune response of mice against EAT, while the efferent phase of the response is accomplished by serum antibodies, perhaps through an interaction with host macrophages.

Comparison between the effects of Micrococcus Lysodeikticus, bacterial cell wall and related polysaccharides in the non-specific tumour immunotherapy of Ehrlich ascites tumour growth

By analyzing, at different times after grafting 300,000 Ehrlich ascites cells to BALB/c mice, the primary immune response to 2.10 8 sheep erythrocytes, the carcinoma monitored immunosuppression was outlined. The fact that murine ascites fluid contains less immunoglobulins and less pre-albumin migrating components than serum of tumour bearing mice suggests that the tumour site may be the consuming focus. When different treatment schedules were assayed, we found that the intraperitoneal route (intratumoral) was better than other treatment routes: for 30,000 initially grafted tumour cells, i.p. treatment with 0.08 and 0.4 mg heat-killed Micrococcus on day 1, 3, 5, 7 and 9 resulted respectively in a 120 and 148% increase in mean life span over control mice and 50 and 20% of long-term survivors were recorded. However, the administration of 1 mg Micrococcus on days 1, 5, 9 and 12 after grafting 300,000 Ehrlich carcinoma cells considerably enhanced tumour growth. The administration of 1 mg of Micrococcus, cell wall, cell wall conjugated chitin, chitin and zymosan A on days 1, 2, 3, 4 and 5 resulted in a 71, 45, 29.5, 68 and 82% increase in mean life span over control mice and 30, 20 and 30% of long-term survivors were recorded for chitin, cell wall conjugated chitin and zymosan A respectively.

Antitumor Agents XXX: Evaluation of α-methylene-γ-lactone-Containing Agents for Inhibition of Tumor Growth, Respiration, and Nucleic Acid Synthesis

Evidence is presented that a number of sesquiterpene lactones isolated from plants and synthesized pyrimidines containing the α-methylene-γ-lactone moiety are potent inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites tumor growth and marginal inhibitors of P-388 lymphocytic leukemia and Lewis lung tumor growth. In vitro aerobic basal respiration and oxidative phosphorylation processes of Ehrlich ascites cells were inhibited by these agents as well as deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic activities. These studies indicate that the α-methylene-γ-lactone moiety, the β-unsubstituted cyclopentenone ring, and the α-epoxycyclopentanone system are the essential moieties for inhibition of these biochemical parameters.