Antitumor activity of carminomycin antibiotic used orally]

Antitumor activity of karminomycin used perorally was studied with respect to 3 strains of mouse transplantable tumors, i. e. one ascitic strain of lymphadenosis NK/LI and two solid strains of lymphosarcoma L10-1 and sarcoma 180. Karminomycin was shown to have a high antitumor activity against the above tumors on its oral administration. In the experiments with lymphadenosis NK/LI the efficiency of karminomycin was higher when it was used perorally as compared to its intravenous administration. It was found that karminomycin had practically the same inhibitory effect on growth of lymphosarcoma L10-1 and sarcoma 180 on its peroral and intravenous administration in doses equivalent by their toxicity.     

Effect of antibiotic therapy and vaccine therapy on the phagocytic reaction in mice infected with Staphylococcus

The time course of changes in the activity, intensity and completeness of phagocytosis with leukocytes of the peritoneal exudate was studied on mice with experimental staphylococcal infection treated with rifampicin, lincomycin and inactivated staphylococcal vaccine used alone or in combination. It was shown that immunization of the animals with inactivated staphylococcal vaccine promoted stimulation of the phagocytic defense. Rifampicin and lincomycin applied therapeutically induced a decrease in the activity, intensity and completeness of phagocytosis. It should be noted that rifampicin had a less pronounced inhibitory effect than lincomycin. The combined use of vaccine and antibiotics with therapeutic purposes promoted an increase in phagocytosis as compared to the use of the antibiotics alone. The combined therapy sometimes resulted in completeness of phagocytosis making it reach the control values (the 10th and 15th days, rifampicin and vaccine). It should be noted that a more pronounced stimulation of the activity, intensity and completeness of the phagocytosis was observed with the use of the combination of rifampicin and the vaccine.     

Preparation of dihydrocarminomycin and a comparison of its antitumor activity with the activity of carminomycin]

A dihydro derivative of karminomycin was prepared using chemical reduction with potassium boron hydride. When dihydrokarminomycin was administered intravenously to healthy albino mice in a single dose it practically showed the same toxicity as karminomycin. However, unlike the latter dihydrokarminomycin induced the death of the animals at later periods of time. Studies on mice with transplantable tumours showed high antitumor activity of dihydrokarminomycin against lymphosarcoma L10-1, sarcoma 180, Garding-Passy melanoma, lymphoid leukosis L-1210 and lymphocytal leukosis P-388. In treatment of the mice with leukosis L-1210 and Garding-Passy melanoma dihydrokapminomycin was much inferior by its efficiency than karminomycin.     

Comparative study of the cardiotoxicity of the anthracycline antibiotics, carminomycin and adriamycin, in white mice]

The cardiotoxic effect of karminomycin and adriamycin administered intravenously for 5 times in equitoxic doses constituting equal portions of LD50 of the respective antibiotic on its single intravenous administration was studied on albino mice. Histological examination of the heart showed that almost identical damages of the myocardium occured after administration of karminomycin and adriamycin in doses of 0.45 of LD50 (1.5 mg/kg) and 0.3 of LD50 (6.3 mg/kg) respectively. The character of the damages due to the antibiotics was close, the most significant changes were observed when the animals were sacrificed 1 month after the last administration of the drug. The histological method is of value in estimation of the cardiotoxic effect of the drugs, using mice as the model suitable for the investigation. Adriamycin had more pronounced cumulative properties as compared to karminomycin: suppression of the weight gain in the mice and their death rate were higher with the use of adriamycin.     

Myeloinhibitory effect of the action of some antitumor antibiotics and its comparative assessment]

General toxic and myeloinhibitory effects of some antitumor antibiotics, such as rubomycin, olivomycin, bruneomycin and karminomycin administered intraperitoneally in a single LD50 to mice were studied. It was found that the general toxicity of bruneomycin and karminomycin was almost the same and 5 to 8 times higher than that of rubomycin and olivomycin. The use of the above antibiotics resulted in definite shifts in the blood systems of healthy mice. The most significant suppression of hemopoesis accompanied by a pronounced depression of the number of the myelocariocytes was observed after the use of olivomycin. The effect of karminomycin was characterized by suppression of erythro-, myelo- and lymphopoesis and depression of the number of the granulocytes and lymphocytes of the blood. Bruneomycin and rubomycin had a short-time myeloinhibitory effect. The erythroid cords of the bone marrow proved to be most sensitive to the inhibitory effect of the antibiotics. However, inhibition of the erythropoesis accompanied by deep reticulocytopenia did not induce the respective depression of the erythrocyte number. The lymphoid cords was in the 2nd place by its sensitivity to the antibiotics and the myeloid and megocariocytal cords were in the 3rd and the 4th places respectively. Complete reduction of hemopoesis in the animals was observed by the 10th day of the drugs use.     

Production and antitumor properties of carminazone

Karminazon (13-benzoylhydrazon) was prepared by condensation of karminomycin with benzoylhydrazine. In its intravenous use in the treatment of mice with lymphosarcoma L10-1 karminazon was less toxic and had lower antitumor activity than karminomycin. Karminazon had a lower selective antitumor activity with respect to lymphosarcoma than karminomycin.     

Comparative cytogenetic action of the antitumor antibiotics, carminomycin and rubomycin

A comparative mutagenic effect of karminomycin and rubomycin in LD50 on the cells of the rat bone marrow (71 animals) was studied. It was found that karminomycin had a higher and more prolonged mutagenic effect than rubomycin. Both antibiotics induced mainly chromatin deletions and not so frequent reconstructions. They are probably identical with respect to their mechanism of action on chromosomes.     

Role of antibiotics in the ecology of actinomycetes]

The organisms producing ristomycin, rifamycin, lincomycin, tobramycin, rubomycin carminomycin, olivomycin, bleomycin and actinomycin D were practically not sensitive to their own antibiotics in the concentrations close to those produced during the biosynthetic process. At the same time other actinomycetous species close to the above organisms were suppressed to a significant extent by their antibiotics in the same concentrations. The experimental data indicated that the antibiotics had a protective effect on the organisms producing them and played a significant role in ecology of the actinomycetes.     

Serum enzymatic activity in oncological patients treated with carminomycin]

Karminomycin effect on the activity of some serum enzymes, such as hexokinase (HK), lactate dehydrogenase (LDG), its isoenzymes and glucose-6-phosphatase (G-6-P-ase) was studied. Biochemical assays were applied to 52 patients with neglected malignant tumors. The course dose of the drug was on the average 72mg. The objective antitumor effect was registered in 15 patients. A reliable increase in the values of LDG-5 and G-6-P-ase was observed after the treatment course in the combined group consisting of all the patients subjected to the biochemical assay. Normalization of the serum enzyme spectrum was observed in 15 patients effectively treated with karminomycin: activity of HK and the cathode fractions of LDG decreased. When treatment with karminomycin was ineffective (37 cases), the changes in the enzymatic activity recorded before the treatment further aggraviated. It was found that the level of G-6-P-ase in the patients' treated with karminomycin increased independent of the treatment effect which was probably associated with its toxic effect on the liver. The increase was reversible.     

Interleukin-12 in anti-tumor immunity and immunotherapy

Interleukin-12 (IL-12) has an essential role in the interaction between the innate and adaptive arms of immunity by regulating inflammatory responses, innate resistance to infection, and adaptive immunity. Endogenous IL-12 is required for resistance to many pathogens and to transplantable and chemically induced tumors. In experimental tumor models, recombinant IL-12 treatment has a dramatic anti-tumor effect on transplantable tumors, on chemically induced tumors, and in tumors arising spontaneously in genetically modified mice. IL-12 utilizes effector mechanisms of both innate resistance and adaptive immunity to mediate anti-tumor resistance. IFN-gamma and a cascade of other secondary and tertiary pro-inflammatory cytokines induced by IL-12 have a direct toxic effect on the tumor cells or may activate potent anti-angiogenic mechanisms. The stimulating activity of IL-12 on antigen-specific immunity relies mostly on its ability to determine or augment Th1 and cytotoxic T lymphocyte responses. Because of this ability, IL-12 has a potent adjuvant activity in cancer and other vaccines. The promising data obtained in the pre-clinical models of anti-tumor immunotherapy have raised much hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity and modest clinical response observed in the clinical trials point to the necessity to plan protocols that minimize toxicity without affecting the anti-tumor effect of IL-12.     

Functional macrophage activity in infection with virulent and avirulent strains of the dysentery microbe

The effect of S. flexneri virulent and avirulent (vaccine) strains 2a on the cytoplasmic membrane of mouse macrophages has been studied by evaluating the action of these bacteria on the activity of 5-nucleotidase. The dynamics of the activity of 5-nucleotidase after the introduction of both virulent and avirulent strains has a phasic character with alternating rises and falls in the activity of this enzyme in comparison with the control. S. flexneri vaccine strain produces mainly a stimulating effect on the functional activity of peritoneal macrophages in mice, which is confirmed by a decrease in the activity of 5-nucleotidase; on the contrary, S. flexneri virulent strain- has mainly an inhibiting effect on the functional activity of peritoneal macrophages, which is confirmed by an increase in the activity of 5-nucleotidase in these cells. The comparative study of changes in the activity of 5-nucleotidase, following the introduction of S. flexneri, in mice, previously immunized with smallpox vaccine, and in intact mice has shown that the use of animals immunized with smallpox vaccine in the study of metabolic characteristics may lead to distortions in the results of the experiment.     

Changes in the phagocytic activity of the peritoneal macrophages of white mice caused by alcoholic intoxication

Observations made on white mice showed that doses of alcohol had a stimulating effect on the indices of macrophage acitivity (pagocytic number and phagocytic index), while longer administration of 40% ethyl alcohol solution (in doses of 0,1 ml for 21--30 days) suppressed the functional activity of macrophages. In vitro experiments in which macrophages were subjected to the action of ethyl alcohol showed that alcohol, depending on its concentration, had a direct effect on the cells of the microphage system.     

Obtaining 14-oxycarminomycin and a study of its antitumor activity

The authors obtained 14-oxykarminomycin by alkaline hydrolysis of 14-bromokarminomycin. On two-fold intravenous administration to mice with lymphosarcoma, strain L10-1, 14-oxycarminomycin showed the same toxicity as karminomycin. The preparation had the same selective antitumor activity as karminomycin.     

Antibiotic therapy of Salmonella infection in infants during the first year of life and methods if its correction]

The efficacy of antibiotic therapy of salmonellosis was studied and functional activity of peripheral blood leukocytes from electron microscopic data was estimated in 200 infants. It was shown that the use of antibiotics in combination with immunostimulants such as leukocyte mass, lysozyme and prodigiozan in complex therapy of salmonellosis in infants had a favourable effect on both the time course of the clinical signs and the functional state of the neutrophil leukocytes. The duration of the treatment decreased by 6.14 +/- 0.34 days and repeated isolation of the pathogen from the host appeared to be less frequent.     

Prevention of the formation of the infectious process with biologically active thymic factors in the Salmonella typhimurium challenge of mice coincident with macrophage activation

A single injection of thymostimulin into mice in a dose of 45 micrograms/kg b.w. enhances the functional activity of macrophages, reaching it maximum on day 10, which prevents the formation of an infectious process in mice challenged with S. typhimurium (LD50). The irradiation of the animals in a sublethal dose leads to the complete abolition of the stimulating effect of thymostimulin on macrophages. The presence of an inducer mechanism of the activation of macrophages by thymostimulin, realized in the production of lymphokines, is suggested.     

Changes in the phagocytic activity of macrophages under the action of different doses of antibiotics]

Penicillin, streptomycin and gentamicin, when introduced into mice in a single injection in doses of 0.5-500,000 U/kg, produced different changes in the phagocytic activity of mouse peritoneal macrophages. Bactericidal doses of these antibiotics either suppressed the activity of macrophages or left it unchanged. Their sub-bactericidal doses enhanced the phagocytic activity of macrophages. Combined use of penicillin and streptomycin produced a synergic effect.     

Apoptotic cells can deliver chemotherapeutics to engulfing macrophages and suppress inflammatory cytokine production

Immunosuppression via cell-cell contact with apoptotic cells is a well studied immunological phenomenon. Although the original studies of immune repression used primary cells, which undergo spontaneous cell death or apoptosis in response to irradiation, more recent studies have relied on chemotherapeutic agents to induce apoptosis in cell lines. In this work, we demonstrate that Jurkat cells induced to die with actinomycin D suppressed inflammatory cytokine production by macrophages, whereas cells treated with etoposide did not. This immune repression mediated by actinomycin D-treated cells did not require phagocytosis or cell-cell contact and thus occurs through a different mechanism from that seen with primary apoptotic neutrophils. Moreover, cells induced to die with etoposide and then treated for a short time with actinomycin D also suppressed macrophage responses, indicating that suppression was mediated by actinomycin D independent of the mechanism of cell death. Finally, phagocytosis of actinomycin D-treated cells caused apoptosis in macrophages, and suppression could be blocked by inhibition of caspase activity in the target macrophage. Together, these data indicate that apoptotic cells act as "Trojan horses," delivering actinomycin D to engulfing macrophages. Suppression of cytokine production by macrophages is therefore due to exposure to actinomycin D from apoptotic cells and is not the result of cell-receptor interactions. These data suggest that drug-induced death may not be an appropriate surrogate for the immunosuppressive activity of apoptotic cells. Furthermore, these effects of cytotoxic drugs on infiltrating immune phagocytes may have clinical ramifications for their use as antitumor therapies.     

Use of carminomycin on adult patients with acute leukemias]

The data on the clinical trials of karminomycin, a new antitumor antibiotic are presented. The drug was used in the treatment of 46 adult patients with leukemia. Karminomycin was used in primary inducing therapy and treatment of relapses. The results of the trials showed that karminomycin had a definite therapeutic activity in treatment of acute myeloblast leukemia at various stages of the process. A rapid effect of the antibiotic provided its use in emergency cases with rapidly progressing variants of the disease.     

The influence of actinomycin D on the activity of delta-aminolaevulinic acid synthetase and dehydratase in the liver of mice and rats treated by griseofulvin.

The changes of delta-aminolaevulinic acid dehydratase--the second enzyme of porphyrin synthesis--were studied and compared in the liver of mice and rats treated with griseofulvin. The results showed that griseofulvin increased the activity of delta-aminolaevulinic acid dehydratase in the liver of mice and rats treated by griseofulvin. No differences were found between mice and rats as to the effect of griseofulvin on the activity of delta-aminolaevulinic acid dehydratase. The influence of the administration of actinomycin D on the activity of delta-aminolaevulinic acid synthetase and dehydratase in the liver of mice and rats was studied at an early period of experimental porphyria induced by griseofulvin. It was found that the administration of actinomycin D blocked the observed effect of griseofulvin on the activity of both enzymes in the liver of mice and rats.     

Mechanism of action of N-acetylglucosaminyl-N-acetylmuramylalanyl-D-isoglutamine on the nonspecific anti-infection resistance of mice

The stimulating influence of glucose-containing muramyldipeptide (GMDP) on the nonspecific resistance of mice was shown to depend on the features of the pathogenesis of the infection. Thus, the intraperitoneal injection of GMDP increased the survival rate of mice infected with Escherichia coli, but had no stimulating effect on the resistance of the animals to Salmonella typhimurium natural infection in whose pathogenesis macrophages played an essential role. Experiments demonstrated that GMDP was capable of enhancing the ingestive function of macrophages, but did not increase their bactericidal activity with respect to this infection.