[Activity of the Russian antitumor compound chlonisol in models of eyelid tumors (experimental study)]. / Aktivnost' otechestvennogo protivoopukholevogo soedineniya khlonizol na modelyakh opukholei vek (eksperimental'noe issledovanie).

Eyelid tumors are the most common neoplasms in everyday ophthalmic practice and cover a wide range of benign and malignant lesions. Surgical methods, cryodestruction, laser therapy and radiation therapy are used in the treatment of malignant eyelid tumors. Chemotherapy does not occupy a prominent place in the treatment of malignant eyelid tumors, its use is limited to sensitive tumors. OBJECTIVE: To assess the antitumor activity of the Russian-developed chemical compound 2-[3-(2-chloroethyl)-3-nitrosoureido]-1.3-propandiol (chlonisol) on the models of transplantable tumors of various histogenesis implanted into the lower eyelid. MATERIAL AND METHODS: The study was carried out on 67 mice of lines 129/SN, BALB/c and C57BL/6 that had Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and B16 melanoma transplanted into the eyelid. Tumor transplantation was done by injecting 0.05 ml of sterile sodium chloride solution containing 106 cells of Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1, or 10% suspension of tumor tissue of B16 melanoma. The injection was performed into the right lower eyelid in the direction from the outer towards the inner corner of the eye using a thin needle (29G). Chlonisol was administered at the maximum tolerated dose of 20 mg/kg or at the lower dose of 15 mg/kg intraperitoneally 24 hours after tumor transplantation. RESULTS: In mice with Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and melanoma B16 transplanted under the skin of the lower eyelid, a single intraperitoneal injection of chlonisol at the dose of 20 or 15 mg/kg caused significant inhibition of tumor growth reaching 100%. Chlonisol significantly increased overall survival in animals with Ehrlich carcinoma (log rank test, p=0.0464), sarcoma 37 (log rank test, p<0.0001), lymphosarcoma LIO-1 (log rank test, p=0.0122) and B16 melanoma (log rank test, p<0.0001); the proportion of animals that were fully healed was 25, 78, 67 and 25%, respectively. CONCLUSION: Chlonisol has a pronounced antitumor effect in mice with Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and B16 melanoma transplanted into the eyelid.

[REPROGRAMMING OF MITOCHONDRIAL ENERGY METABOLISM IN MALIGNANT NEOPLASMS].

The novel ideas of fundamental role of mitochondria in the maintenance of viability of malignant cells have been reviewed. The modern state of research is considered in detail, including: mitochondrial control of the cellular redox state, sites of reactive oxygen species (ROS) production in inner mitochondrial membrane and antioxidant protection systems. Specificities of the structural-functional mitochondrial remodelling in malignant tumors, the mechanisms of the energy metabolism reprogramming, enhancement of the ROS production and adaptation to the hypoxic conditions and metabolic stress are analyzed. The available data including our research on transplanted tumors indicate that cytotoxic action of sodium dichloroacetate (the inhibitor of pyruvate dehydrogenase kinase) depends on biological properties of tumors and intensity of structural-functional mitochondrial rearrangement. Dichloroacetate turned out to be effective for sarcoma 37, but not for Lewis lung carcinoma.

Experimental study of the effects of metal nanoparticles on tumor growth and bone marrow hemopoiesis.

Metal (Zn, Cu, Fe) nanoparticles, particularly Zn, induce regression of transplanted sarcoma 37 and increase the percentage of dead and degenerated cells. Antitumor effect of metal nanoparticles was not associated with leukopenia or coarse bone marrow abnormalities, but differential leukocyte and bone marrow counts remained changed.

The influence of sodium dichloroacetate on the oxidative processes in sarcoma 37.

AIM: to study the activity of antioxidant enzymes and to evaluate an intensity of prooxidant processes in sarcoma 37 (S37) cells during tumor development and under influence of sodium dichloroacetate (SDA). METHODS: Activity of total superoxide dismutase (SOD), SOD isoforms, catalase (Cat), glutathione peroxidase (GP), and glutathione reductase (GR), as well as content of reduced glutathione (GSH) and lipid peroxidation (LP) secondary byproducts were determined in S37 homogenated tissues of untreated mice and animals treated with SDA at daily dose of 86 mg/kg. RESULTS: SDA treatment of S37-bearing mice resulted in the reduced activities of total SOD, SOD isoforms (especially Mn-SOD), Cat, GP and significantly decreased GSH content on the background of LP intensification in tumor tissue. CONCLUSION: The observed changes of oxidative homeostasis in S37-bearing animals treated with SDA could be considered as an element of antitumor action of SDA.

Influence of bacterial lectins on some reactions of nonspecific immunity in sarcoma 37 transplanted mice.

AIM: To study preventive effect of cytotoxic lectin from Bacillus subtilis B-7025 on the tumor growth and nonspecific immunity in sarcoma 37 transplanted mice. METHODS: Sarcoma 37 cells were transplanted in Balb/c mice. Cytotoxic lectin (CL) was isolated from cultural fluid of B.subtilis strain B-7025 and inoculated at a dose of 0.2 mg per animal in prophylactic or combined schedule. Functional activity of macrophages was evaluated by NBT-test and the level of cytotoxicity, cytotoxic activity of splenocytes was assayed against K562 cells. RESULTS: CL administration in prophylactic or combined schedule results in inhibition of sarcoma 37 growth in mice. Stimulating effect of CL on peritoneal macrophages of sarcoma 37-bearing mice, especially at early stages of tumor growth, has been observed. At the late stage of tumor growth, the effect of lectin on cytotoxic activity of spleen mononuclear cells has been registered. CONCLUSION: Upon the use of lectin from B. subtilis B-7025, positive shifts of antitumor immunity reactions leading to tumor growth inhibition and elevation of average life span of tumor-bearing mice, have been detected.

[Antineoplastic properties of extracellular fructoso-1,6-bisphosphatase of Bacillus subtilis 668 and preparation isolated from cultural liquids of Bacillus subtilis 7025].

It was shown for the first time that extracellular FBPase of B. subtilis 668 like the preparation obtained from culture liquid of B. subtilis B 7025 displays citotoxicity activity in respect of tumor cells of sarcoma 37 in vitro. It is shown that the preparations remove TA antigens from the surface of the tumor cell. It is supposed that the mechanisms of citotoxic effect of extracellular FBFase of B. subtilis 668 and preparation from the culture liquid of B. subtilis B 7025 in vitro on cells of sarcoma 37 is probably realized through the apoptosis.

[Influence of probiotic subalin on efficiency of antitumor vaccine].

Preparation subalin created on the basis of a recombinant strain of B. subtilis 2335/105 containing the gene of synthesis of human a-2-interferon has been tested in the experiment for its ability of increasing the efficiency of antitumor vaccine prepared from syngenic tumor cells and cytotoxic lectin--the metabolism product of the strain of B. subtilis B-7025. On the models of Lewis lung carcinoma of C57B1 mice and sarcoma-37 of Balb/c mice it was shown that the complex use of the antitumor vaccine and subalin makes for the more efficient tumor growth suppression and survival of treated animals as compared with the separate use of autovaccine or subalin. The prospects and expediency of the complex use of vaccine and subalin at malignant tumors immunotherapy were established.

Actividad antitumoral de una mezcla de polisacáridos obtenida de la especie Argemone mexicana L / Antitumoral activity of a mixture of polysaccharides obtained from Argemone mexicana L. species

En la actualidad, las plantas constituyen la principal fuente de obtención de la mayoría de los fármacos que pueden ser útiles para el tratamiento del cáncer. Se realizó la extracción de una mezcla de polisacáridos a partir de hojas de la planta Argemone mexicana L., conocida como Cardo Santo, colectada en el período de floración. Se empleó el método de incorporación de Timidina tritiada para determinar el efecto de la mezcla sobre la proliferación celular en líneas celulares humanas (H125 y U1906). La actividad antitumoral de este crudo de polisacáridos, administrado solo o combinado con 2 citóstaticos conocidos, se evaluó en ratones inoculados con células tumorales de Leucemia Linfocítica P-388 y Sarcoma 37 y su actividad antitumoral indirecta se valoró en el tumor ascítico de Ehrlich. En todos los casos se calculó el aumento del tiempo de sobrevida respecto al patrón de comparación positivo o negativo. La mezcla de polisacáridos provocó rechazo a la implantación del tumor de Ehrlich y su administración conjunta con el citóstatico 5 Fluoracilo produjo un incremento moderado de la actividad antitumoral en los ratones portadores del tumor Sarcoma 37. Estos resultados pudieran estar relacionados con el posible efecto estimulador de esta mezcla sobre el sistema inmune de los animales con tumor. Es necesario estudiar el efecto sobre el sistema inmune de la mezcla de polisacáridos obtenidos de la especie A. mexicana y la efectividad de su combinación con otros citostáticos, para determinar su posible uso como adyuvante de la quimioterapia para el tratamiento del cáncer(AU)

[The EPR spectra of the ribonucleotide reductase in the tumorous tissues and organs of tumor-bearing animals]. / Spektry EPR ribonukleotidreduktazy v opukholevykh tkaniakh i organakh zhivotnykh-opukholenositelei.

Ribonucleotide reductase activity (RRA) has been studied in various tumors and spleens of tumor-bearing animals using EPR technique and biochemical methods. The effect of a number of biologically active compounds on RRA has also been studied. RRA in tumor and spleen increases during tumor growth. Inhibitory effect of irradiation, hydroxyurea, nitrosomethylurea and activatory effect of 5-nitrofurans and nitroimidazole derivatives on RRA has been observed. Regulatory factors of RRA and DNA synthesis in vivo have been discussed.

The effect of a bacterial vaccine on tumors and the immune response of ICR/Ha mice.

This study examined the effect of mixed bacterial vaccine (MBV), a biological response modifier prepared from Streptococcus pyogenes and Serratia marcescens, on the immune system of mice and on the regression of a transplantable mouse tumor sarcoma 37. The study examined MBV's biological properties and analyzed its chemical composition. The chemical composition varied with the growth media. A typical centrifuged, dialyzed supernate of the serum-containing preparation was found to consist mainly of protein and minimal amounts of carbohydrate and endotoxin, while MBV made with synthetic medium contained similar amounts of all three. MBV was nontoxic for mice, which gained weight following the injection of 0.5-1.0 ml of MBV. MBV caused regression of 20-100% of well-established mouse tumors without appreciable toxicity. MBV also had a striking effect on the immune response of mice to sheep red blood cells. When administered simultaneously with antigen injection, MBV increased the number of antibody-secreting splenocytes measured by the plaque-forming assay threefold. Serum antibody levels also increased two- to threefold. MBV did not enhance the immune response to pneumococcal polysaccharide type III, a B-cell-dependent response. However, the in vivo administration of MBV increased the in vitro response to MBV and the B-cell mitogen lipopolysaccharide. MBV compares favorably with other biological response modifiers because of its enhancing effect on the immune response and its oncolytic properties at nontoxic levels.

[Studies on antitumor drugs: the synthesis of N',N"-dispirotripiperaziniums].

In order to search for new antitumor drugs, sixteen N',N"-dispirotripiperazine derivatives were synthesized from N',N"-dispirotripiperazinium dichloride dihydrochloride by substitution, acylation and Mannich reaction. Six compounds were selected for preliminary pharmacological test. The result showed that five compounds possess inhibitory action against carcinoma S37 in rats. The inhibitory activity of compounds VI and X was 55.0% and 41.9% respectively.

[Changes induced by sarcolysine in vivo in the composition of DNA-bound lipids in sarcoma 37]. / Izmenenie sostava DNK-sviazannykh lipidov sarkomy 37, indutsirovannoe sarkolizinom in vivo.

The two DNA fractions were isolated from sarcoma 37 by the use of the phenol method: supramolecular complex of DNA (SC DNA, 60%) and "phenol" nuclear matrix DNA (PNM DNA, 40%). The lipids in SC DNA represented of light and tightly bound components, the latter was similar to the lipid composition of PNM DNA. SC DNA contains 20 micrograms of neutral lipids (NL) and 6.5 micrograms of phospholipids (PL), while PNM DNA contains 9.8 micrograms of NL and 3.5 micrograms of PL per mg DNA. SC DNA-bound lipids of sarcoma 37 are deficient in free cholesterol (FC, 13%), but rich in cholesterol esters (CE, 39%) and free fatty acids (FFA, 23%); very rich in cardiolipin (CL, 43%) and phosphatidylethanolamine (PE, 28%), but deficient in phosphatidylcholine (PC, 12%). The tumor contains triglycerides (TG) that is absent in DNA of the normal cells. The injection of sarcolysine (10 micrograms/kg) markedly increased (1.5-3 times) the content of all LN and PL fractions in SC DNA, which was accompanied by both the accumulation of FC, TG, PC and the reduction of the remaining lipid fractions in PNM DNA. It is supposed, that DNA-bound lipids may be the target for the action of sarcolysine.

[Blood flow in normal and tumor tissue during hyperthermia]. / Krovotok v normal'nykh i opukholevykh tkaniiakh pri gipertermii.

The authors reported the results of measurements of the blood flow in subcutaneous fat and 3 types of tumors (sarcoma 37, Lewis carcinoma, melanoma B16) by a thermoelectric method during local hyperthermia of mouse limbs. In the first minutes of exposure the blood flow rate increased reaching a plateau in 25-35 min. Changes in the blood flow grew with raising the temperature of heating, and they were more noticeable for normal tissues than for tumorous ones. The blood flow enhancement varied in different tumors: the highest in sarcoma 37, and the lowest in melanoma B16. In some tumors after prolonged heating (over 30 min.) and at high temperature (44 degrees C) a maximum increase in the blood flow was followed by its weakening.

[Action of khanerol on the superhelical DNA structure of S-37 cells]. / Deistvie khanerola na superspiral'nuiu strukturu DNK kletok S-37.

The damaging effects on the structure of a supramolecular DNA complex of sarcoma-37 cells in mice following the use of the therapeutic doses of khanerol were found. Capillary elastoviscosimetry and nucleoid sedimentation procedure showed that the damage of the supramolecular DNA complex structure becomes apparent already after 4 hours, and increases by 24 hour. In studies of the binding of khanerol with DNA by Cd and Tmelt. the procedure showed direct interaction of khanerol with DNA. The role of conformational changes of the supramolecular DNA complex in the cytotoxic action of antitumour agents is discussed.

[Structural differences of the supramolecular DNA complex from tumor strain cells]. / Strukturnye razlichiia nadmolekuliarnogo kompleksa DNK iz kletok opukholevykh shtammov.

Elastoviscosimetric examination was carried out to study the structure of supramolecular DNA complexes obtained from transplantable tumor strain cells and those of the same strains showing pronounced growth in synthetic culture media. The supramolecular DNA complex was isolated as a nucleoid and examined by ethidium bromide elastoviscosimetric titration method. Levels of supercoiled DNA were found to be significantly lower in the chromatin of cells of in vitro growing strains, as compared to parental strain cells where the said type of DNA predominated. Two patterns of DNA compact packing--supercoiled-domain and one characterized by a faster bond between DNA and non-histone proteins, and single-stranded DNA areas preexisting in domains--were suggested.

[Traditional Chinese and Western medicine in the treatment of 27 patients with malignant lymphoma].

Twenty-seven patients with malignant lymphoma (14 Hodgkin's disease, 9 histiocytosarcoma, 2 plasmacytoma, 2 lympholeucosarcoma) were treated by Ailin-injection plus Chinese herbal medicine. The latter's composition and dose varied depending on the clinical manifestations. All the patients had stage III and IV lesions. The total remission rate was 70.37% (complete remission 13 patients, partial remission 6 patients, no remission 8 patients). In addition, we also studied the suppressive effect of Ailin on transplanted tumor in vivo (S-180). The suppression rates were 36.09%, 48.80%, 32.67% by three repetitions with an average of 39.18% (P less than 0.002). They were 37.25%, 35.29% on S37 with an average of 36.27% (P less than 0.005). They were 46.53%, 44.56%, 51.35%, 45.95% on Ehrlich ascites tumor cells with an average of 47.09% (P less than 0.001). The clinical and experimental studies suggest that Ailin-1 has no serious side effects and is well tolerated by patients with malignant lymphoma at moderate or advanced stages. No toxic reactions were observed at the clinical dose. In the above combination therapy, the Chinese herbal medicine has obvious supplementary effect in the treatment of the patients' cachexia and immuno-suppression.

[Combined effect of interferon inducers, radiosensitizing and antineoplastic agents on solid tumors]. / Sovmestnoe deistvie induktorov sinteza interferona, radiosensibiliziruiushchikh i protivoopukholevykh agentov na solidnye opukholi.

In experiments with mice bearing solid sarcoma 37 a study was conducted on the combined effect of radiation and inductors of endogenous interferon synthesis (IEIS), together with hyperthermia or together with an alkylating and carbomoilating agent, dimethinur. The effect was estimated by the tumor growth coefficient and by the number of animals with the regressed tumors. Po I. polyC was not shown to influence the efficiency of hyperthermia combined with radiation; dextransulphate and tiloron increased the radiosensitizing effect of hyperthermia. Dimethinur aggravated the effect of radiation, but with IEIS used together with dimethynur and radiation, the response of the tumor increased insignificantly as compared to the effect of IEIS together with radiation.