Modification of antitumor effect of vincristine by natural avermectins]

The effect of avermectins (aversectin C, aversectin C1 and avermectin B1) on the vincristine antitumor action with respect to murine transplantable tumors was studied. It was shown that both the natural avermectins mixtures and the individual avermectin B1 potentiated the antitumor action of vincristine on Ehrlich carcinoma, melanoma B16 and P388 lymphoid leukemia, including the vincristine resistant strain P388. Such an effect of the avermectins was observed only when they were administered after vincristine.     

Action of avermectins on lymphoid leukemia P-388 cells in vitro]

Avermectins are final products in the fermentation process with Streptomyces avermitilis. They have parasitocidic activity and are used as the main substances of insectoacaronematocides. The study of the activity of the natural avermectin complex (aversectin C) and separate avermectins A1, A2, B1 and B2 in the cell culture of lymphoid leukemia P-388 showed that within the concentrations of 0.1 to 1.0 microgram/ml aversectin C inhibited the growth of the tumor cells and induced their death. The inhibition was due to blocking the cell mitosis. The cell death was accompanied by internucleosomal degradation of the DNA nuclei i.e. the death was of the apoptosis type. The sensitivity of the cells to aversectin C was directly proportional to their initial proliferative activity. As for the separate avermectins only avermectin A1 had the cytotoxic activity within the concentrations used, avermectin A2 had the cytostatic activity and avermectins B1 showed no activity under the experimental conditions.     

Cytotoxic and cytostatic effect of avermectines on tumor cells in vitro]

Effect of natural avermectin complex (aversectin C) and separate avermectins A1, A2, B1 and B2 in the cell culture of murine myeloma Ns/o, Erlich carcinoma ascites and human larynx carcinoma Hep-2 was investigated. It was shown that aversectin C within the concentrations of 0.1 to 1.0 mcg/ml inhibited proliferation of tumor cells and induced their death. Proliferation inhibition was due to the delay of the cells cycle start (lag-phase prolongation) and blocking of mitotic cycle. Ns/o cells death had apoptosis signs: chromatin condensation and fragmentation, DNA fragmentation. It was demonstrated that only avermectin A1 has cytotoxic activity within the concentrations used, avermectins A2 and B2 had cytostatic activity, avermectin B1 showed no activity under the experimental conditions.     

Selective cytostatic and cytotoxic effects of avermectins]

A natural avermectin complex, aversectin C, was shown to be capable of exerting selective cytostatic effect. It killed proliferating neuroblastoma B 103 cells but was non-toxic for differentiated cells of this culture. The activity of aversectin C was related neither to activation of the GABA alpha-receptors nor to their blocking and was at a large extent due to the action of avermectin A1, a component of aversectin C.     

Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment

The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.     

Selective Cytostatic and Neurotoxic Effects of Avermectins and Activation of the GABAα Receptors

A natural avermectin complex, aversectin C, was shown to be capable of exerting selective cytostatic and neurotoxic effects on mammalian cells. Specifically, it killed proliferating neuroblastoma B103 cells but was non-toxic for differentiated cells of this culture. The anti-proliferation action of aversectin C was not inhibited by bicuculline or picrotoxin, antagonists of the GABA receptors, and was partly due to the action of avermectin A₁, a component of aversectin C. Aversectin C irreversibly suppressed activity of 60% neurons in medial septal slices of the rat brain. More than 55% of them were the GABA- and B₁-sensitive neurons whereas the rest, about 45% neurons, were the GABA-insensitive and the neurotoxic effect of aversectin C was caused mainly by the B₂ component.     

Effect of avermectns on Ca(2+)-dependent chloride currents in plasmalemma of Chara corallina cells]

A natural complex of avermectins, aversectin C, and a component of this complex, avermectin A1, were shown to change the conductivity of Ca(2+)-dependent chloride channels of plasmalemma of Chara corallina cells by acting only from the outer side of the cellular membrane. Low concentrations of aversectin C and avermectin A1 increased the chloride current: K1/2 = 3.5 x 10(-5) mg/ml for the whole complex and K1/2 = 2.1 x 10(-3) mg/ml for A1. Relatively high concentrations of the compounds suppressed the chloride current: K1/2 = 2.2 x 10(-3) mg/ml for aversectin C and K1/2 = 4.2 x 10(-6) mg/ml for A1. The Hill coefficients for the interaction of avermectin A1 with the corresponding targets for stimulation and suppression of the chloride current were 2.8 and 2.5 respectively. Bicuculine, a non-specific inhibitor of the GABA alpha-receptors, did not influence stimulation of chloride currents caused by action of low concentrations of avermectins, but at the same time blocked suppression of the chloride currents associated with the action of high doses of avermectins. Avermectins A2, B1 (abamectin), B2 and 22,23-dihydroavermectin B1 (vermectin) in the concentration range studied, did not affect the chloride currents of Chara corallina cells.     

The effect of ascitic fluid on the growth of Ehrlich tumor and Lewis carcinoma]

In the study of the effect of ascitic fluid and dialysate of Ehrlich ascites tumor cells (m.m. less than 15 kDa) on the growth of Ehrlich and Lewis carcinoma it was found that the ascitic fluid significantly decreased the size of Ehrlich tumor (by more than 50% on day 9-25 after the tumor cell inoculation). It also reduced Lewis carcinoma tumor volume by more than 30% during 3 weeks after the tumor cells inoculation. Dialysate of Ehrlich tumor cells significantly inhibited the growth of Ehrlich tumor too. It is suggested that this test-system simulates inhibition of a small tumor by a big tumor in vivo.     

The modelling of the growth of Ehrlich carcinoma and teratoma T-36 with ascitic fluid and tumor-cell dialysate]

The study of the effect of ascitic fluid and dialysate of Ehrlich ascites tumor cells (M.m. less than 15 kDa) on the growth of Ehrlich carcinoma and teratoma T-36 has shown that both the ascitic fluid and dialysate can protect tumor cells in vivo. The number of animals with tumors increased from 0% in control animals to 60 and 20%, respectively, in experimental ones after transplantation i.m. of 20 x 10(3) Ehrlich tumor cells into mice. Compared to control, ascitic fluid and dialysate of Ehrlich ascites tumor cells increased the rate of tumor growth to 195 and 153%, respectively. It is suggested that this test-system simulates the effect of tumor humoral factors in vivo.     

The effect of ascitic fluid globulins on the growth of leukemia P388/DOX and Ehrlich's carcinoma in mice]

The study was performed to investigate the effect of ascitic fluid globulins of tumor on tumor growth and life span of mice. The globulins are shown to shorten the life span of Ehrlich tumor mice from 86.8 to 61.8 days, to increase 3-5-fold the growth rate of Ehrlich carcinoma and P388/DOX tumor. It was found that globulins of ascitic fluids and serum globulins of tumor have equal effects of tumor growth. It is proposed to use globulins of ascitic fluid to study the globulin role in tumor growth.     

Synthesis and antitumor properties of 3'-desamino-3'-dimethylformamidinorubomycin

Interaction of rubomycin (daunorubicin) chlorhydrate with dimethylformamidine diethyl acetal yielded 3'-desamino-3'dimethylformamidinorubomycin chlorhydrate (DFR). Comparative antitumor activity of DFR and rubomycin was studied on mice with respect to ascitic lymphadenosis NK/Ly and Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388 and two solid tumors i. e. lymphosarcoma LIO-I and sarcoma 180. The highest antitumor effect of DFR was observed in the mice with Ehrlich carcinoma and lymphadenosis NK/Ly after the drug intravenous administration for 4 times. By selectivity of the antitumor effect DFR was inferior to rubomycin with respect to lymphosarcoma LIO-I and sarcoma 180. It was shown that the antileukemic activity of DFR and rubomycin with respect to hemocytoblastosis La was practically the same. In the experiments with leukemia P-388 DFR was inferior to rubomycin.     

The Effect of Irradiation with a Sequence of Neutrons and Protons on the Tumor Response of Solid Ehrlich Carcinoma and Skin Reactions in Mice in the Early and Long Terms

Biophysics - The effects of combined irradiation with a sequence of protons at a total dose of 80 Gy and neutrons at a dose of 5 Gy of a solid form of ascitic Ehrlich carcinoma on the response of...     

Schizonellin A and B,new glycolipids from Schizonella melanogramma

Two new glycolipids, schizonellin A and B, were isolated from cultures of the smut fungus Schizonella melanogramma. Their structures were elucidated by chemical degradation and spectroscopic methods. The schizonellins are active against Gram-positive bacteria, as well as against some Gram-negative bacteria and some fungi. DNA-, RNA- and protein-syntheses in Ehrlich carcinoma ascitic cells are inhibited simultaneously after addition of the schizonellins. Strong haemolytic action on bovine erythrocytes was observed.     

The bradykinin B1 receptor antagonist R-954 inhibits Ehrlich tumor growth in rodents

The present study investigated the effects of a new bradykinin B₁ receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.6-fold), and blood (12.6-fold). R-954 (2 mg/kg, s.c.) significantly reduced the ascitic fluid volume (63.7%) and the mouse weight gain (30.5%) after 10 consecutive days of treatment. The B₁ antagonist as well as the anti-neoplasic drug vincristine also significantly inhibited the increase in total cell count in bone marrow, ascitic fluid, and blood. R-954 reduced significantly the total protein extravasation (57.3%), the production of nitric oxide (56%), PGE₂ production (82%), and TNFα release (85.7%) in mice peritoneal cavity whereas vincristine reduced the release of these inflammatory mediators by 84-94%. The increase in paw edema after intraplantar injection of EAT cells was reduced by approximately 52% by either R-954 or vincristine treatment. In conclusion, this study presents for the first time the antitumoral activity of a new bradykinin B₁ receptor antagonist on ascitic and solid tumors induced by Ehrlich cell inoculation in mice and rats.     

Solid intraperitoneal Landschütz tumour in mice: implications in cancer chemotherapy and immunology studies.

Multiple intraperitoneal injections of various normal sera into BALB/c mice inoculated intraperitoneally with Landschütz ascites tumour cells abrogated the development of ascitic syndrome in almost all the animals. In a large proportion of the survivors solid intraperitoneal tumours developed, composed of characteristic ascites tumour cells engulfed and encapsulated in connective tissue. The effect of serum on the development of the solid tumour was diminished if the donor had been immunized against mouse IgG. Inoculated animals treated with serum hyperimmune against mouse IgG showed accelerated ascitic tumour growth. Cyclophosphamide or arabinosylcytosine strongly inhibited growth of solid tumours. Simultaneous administration of arabinosylcytosine and its antagonist cycloheximide did not interrupt tumour growth.     

Effects of Pfaffia paniculata (Brazilian ginseng) extract on macrophage activity

The roots of Pfaffia paniculata (Brazilian ginseng) have been indicated for the treatment of several diseases and as an analgesic and antiinflamatory drug. Treatment of mice with 200 mg/kg of the powdered root of P. paniculata reduced the Ehrlich ascitic volume [Matsuzaki, P., Akisue, G., Salgado Oloris, S.C., Gorniak, S.L., Zaidan Dagli, M.L., 2003. Effect of Pffafia paniculata (Brazilian ginseng) on the Ehrlich tumor on its ascitic form. Life Sciences, Dec 19; 74 (5), 573-579.]. One of the putative means to control the Ehrlich tumor growth is by increasing macrophage activity [Kleeb, S.R., Xavier, J.G., Frussa-Filho, R., Dagli, M.L.Z., 1997. Effect of haloperidol on the development of the solid Ehrlich tumor in mice. Life Sciences, 60 (4/5), 69-742.]. The aim of this study was to investigate experimentally the effects of the methanolic extract of P. paniculata roots on macrophage activity. Male mice received, by gavage, once a day, different doses (100, 250, or 500 mg/kg) of the methanolic extract of P. paniculata or filtered water, as control, for 10 days. Macrophage activity was evaluated through the phagocytosis index (PI), spreading index (SI), production of peroxide oxigen and nitric oxide. The peritoneal cells were activated with ip inoculation of Ehrlich ascitic cells, 24 h before the macrophage harvesting. The methanolic extract raised significantly the SI of mice from group of 500 mg/kg in comparison with the control group and group of 100 mg/kg. This raise of SI possibly induced the higher phagocytic activity observed in the experimental situation. Increased macrophage activity may be one of the effects contributing to inhibition of the Ehrlich ascitic tumor growth in mice.     

Antitumor activity of the components of a carminomycin complex

The antiblastomic activity of the carminomycin complex components was studied with respect to 8 strains of transplantable tumors of mice: lymphosarcoma L10-1, prestomach cancer OZh-5, sarcoma 180, lymphoid leucosis L 1210, lung bronchogenic cancer RL, lymphodenosis NK/LI, Ehrlich carcinoma and Garding-Passy melanoma. It was shown that components I, II and III possessed almost the same high antiblastomic activity and the same optimal administration schemes should be used for them. The scheme consisted of two-fold administration of the drug at intervals of 96-120 hours. Component I had broader therapeutic ranges and was more active against the lung bronchogenic cancer as compared to component II. All 3 components had no selective antiblastomic effect on the ascitic form of Ehrlich carcinoma. A comparative study of the component toxicity and pharmacology is required for final conclusion as to the recommendation of one of the components for clinical trials.     

Antibiotics from basidiomycetes

Three new antibiotically active metabolites were isolated from cultures of the fungus Pleurotellus hypnophilus. The structures which are closely related to the coriolins were elucidated by spectroscopic methods. Hypnophilin (1) has a hirsutane sceleton whereas pleurotellol (2) and pleurotellic acid (3) are sesquiterpenoids with novel hirsutane skeletons. The common structural feature of all three metabolites is an -methylene ketone moiety. The antibiotics inhibited the growth of several bacteria as well as of some fungi. In cells of the ascitic form of Ehrlich carcinoma RNA and DNA syntheses were more affected than protein synthesis. The mode of action was compared with the antimicrobial and cytotoxic effects of complicatic acid (4) and other -methylene ketones and lactones from higher plants. All the compounds tested reacted rapidly with cysteine to form adducts which were almost devoid of biological activity.Abbreviations ECA-cells Ehrlich carcinoma ascitic cells - MIC Minimal inhibitory concentration - MNNG N-methyl-N-nitro-N-nitrosoguanidine Antibiotics from Basidiomycetes. XIII. T. Anke, W. H. Watson, B. M. Giannetti, and W. Steglich: The alliacols A and B from Marasmius alliaceus (Jacq. ex Fr.) Fr. J. Antibiotics, submitted     

The problem of enhancing the biological action of ionizing radiations. Glucose as an agent for increasing the radiosensitivity of Ehrlich ascitic carcinoma cells in vitro

The effect of short-term incubation of Ehrlich ascites tumor cells in a medium containing excess glucose on their radiosensitivity was studied with a reference to the growth of tumors of ascitic and solid forms. It was shown that the incubation of cells with glucose, being accompanied by a change in pH of the suspension, caused, by itself, only a slight increase in the duration of the latent period of solid tumor formation and in the life-span of mice with ascitic tumors but increased considerably the lethal effect of radiation, as was estimated by the above mentioned criteria and the percentage of inoculated tumors.     

In vivo action of valinomycin on Ehrlich ascites tumor cells. Inhibition of the proliferative activity of the tumor cells under the action of valinomycin]

It was shown that repeated administrations of valinomycin in doses of 1.0 and 0.01 gamma/gm to mice with Ehrlich ascitic tumors inhibited the ascite development. The radioautographic study using 3H-thimidine showed that 24 hours after the administration of valinomycin in doses of 0.1 and 0.01 gamma/gm transference of the cells into the phase of DNA synthesis was inhibited--inhibition of the tumor cell mitotic activity took place.