Anti-tumour agent

FIELD: medicine.

SUBSTANCE: invention represents an anti-tumour agent containing glucocorticoid hormone in an amount of 0.3 mcg%-40 mcg%, very low-density lipoproteins in an amount to provide the apolipoprotein E content in a formulation of not less than 1 mg%, and additionally a physiologically acceptable solvent, which can be used to inhibit the tumour growth by initiating the tumour cell apoptosis.

EFFECT: higher effectiveness of the antitumour agent and extended indications for use.

2 cl, 3 ex, 6 tbl, 5 dwg

 

The invention relates to medicine and veterinary medicine, in particular to cancer, and can be used to suppress tumor growth by triggering apoptosis of tumor cells in experimental and clinical Oncology.

Lipoproteins transport form of drugs, including drugs that have been used in various works. It is believed that the uptake of lipoproteins by tumor cells is significantly higher than healthy (1). Actively proliferating tumor cells have an increased need for lipids. In addition, the rapid capture of lipoproteins due to the large number of receptors to him on the cell membranes (2).

Known antitumor agent, including low-density lipoprotein (LDL) or high density lipoprotein (HDL) in combination with cytotoxic drugs (5-fluorouracil, 5-iododeoxyuridine, doxorubicin, vindesine) and used to suppress tumor growth of cervical cancer and breast cancer (3). A disadvantage of the known antitumor agents is that its application is limited gormonzavisimym tumors (cervical cancer and breast cancer), it has a limitation with respect to tumors of other origin. Another disadvantage of the known tool is that its effect is not sufficient for active suppression of cell proliferation.

Known antitumor agent, representing particles containing low-density lipoprotein (LDL) and lipophilic derivative of cytostatics. As cytostatic used methotrexate or 5-fluorodeoxyuridine (FIT). Lipophilic derivative of cytostatic produced synthetically on the basis of oleic acid. One LDL particle includes 30 molecules moneyinbag derived FIT (4). A disadvantage of the known tool is its low efficiency, toxicity of cytostatic and complex production technology.

Known antitumor agent, comprising the antitumor agent paclitaxel and emulsion, rich in cholesterol (low density lipoprotein) in a molar ratio of 1:6. Mixing the two components increased the particle size at 50%, but did not affect the chemical structure of the cytostatic. This complex enters the tumor cell with the participation of receptors for low density lipoproteins. The complex is stable and has cytotoxic activity, the drug shows less toxicity in rats. The reduction of side effects and transport of paclitaxel in the tumor tissue can be recommended low-density lipoprotein (LDL) as adjuvant for drugs (5). The effectiveness of the funds is confirmed the patient is with breast cancer (6). A disadvantage of the known means is that paclitaxel has a limited indications for use, is not included in the list of the most active anticancer drugs.

Known antitumor agent, comprising albumin and paclitaxel, in forming a mixture of nanoparticles with a size of about 130 nm, which makes it suitable for intravenous administration. Clinical trials have shown its effectiveness in breast cancer, including the stage of metastasis in patients for whom therapy anthracyclines not shown (7). The disadvantage of analogue are limited indications for use, because albumin as the carrier does not have a high directivity actions in relation to tumor cells.

Known means, including lipoproteins, lipopetides and their analogues containing lipopeptide somocystinamide A (somocystinamide A), as well as the use of liposomes containing them, for the induction of apoptosis in normal or cancer cells or slowing tumor-associated blood vessels (capillary endothelium) (8). The disadvantage of this analogue is a complex composition of high complexity on the acquisition phase of the carrier. In addition, liposomes are rapidly destroyed in the peripheral blood and may not be effective carriers of cytotoxic agents.

Known protivoop Evoe means, representing stable nanoparticles comprising a cytostatic agent, a biodegradable polymer, surfactant, cryoprotector and vector molecule for targeted delivery of particles into the affected organs and tissues. As cytostatic used paclitaxel, as a vector molecules for targeted delivery of particles into the affected organs and tissues - From-terminal domain of alpha-fetoprotein (rdfp) (9). Lack of funds is the use of paclitaxel as an anticancer drug, not possessing a broad spectrum of action, as well as technical complexity and the complexity of receiving antitumor agents, the more expensive the cost of the final product.

The disadvantage of all funds described in the treatment of tumors is the use of cytostatics - alien chemical compounds that have significant toxic effect on the body. This treatment is accompanied by the development of severe complications such as organoclorados with severe functional deficiency of organs and systems.

Closest to the claimed is an antitumor agent for the treatment of chronic lymphocytic leukemia, including apolipoprotein E4 (apoE) - containing very low density lipoproteins (VLDL) in combination with a steroid hormone. As a steroid hormone used ect ageny or androgens. The authors intend to use VLDL containing specific genotype apoE - apoE. To enhance antitumor activity in women with lymphocytic lymphoma additionally introduced estrogens, male androgens. The presence apoE in VLDL must be confirmed by genotyping (10, prototype). The disadvantage of the prototype is the lack of effectiveness of the known means, a narrow range of funds committed, restricted hormone-dependent tumors, it is ineffective for the treatment of other cancers, such as liver tumors.

An object of the invention is to increase the effectiveness of antineoplastic agents, the extension of the indication for use.

The solution of this problem is achieved by the fact that suppression of tumor growth by triggering apoptosis of tumor cells claimed antitumor agent as a steroid hormone includes hormone from the group of glucocorticoids in the amount of 0.3 μg % - 40 mg %, VLDL - in an amount to provide the content of apolipoprotein E in the formula and not less than 1 mg %; the tool further comprises a physiologically acceptable solvent; as it includes glucocorticoids cortisol or its analogs.

Description of the invention

Declared Ave is tivaouane means includes glucocorticoid hormone in the amount of 0.3 μg % - 40 mg %, VLDL - in an amount to provide the content of apolipoprotein E in the formula and not less than 1 mg %; the tool further includes a physiologically acceptable solvent; as it includes glucocorticoids cortisol or its analogs.

As analogues of cortisol declared the tool may include, for example, corticosterone, tetrahydrocortisol or their synthetic derivatives.

The composition of the funds may be included native or synthetic very low density lipoproteins (VLDL).

Native VLDL obtained by ultracentrifugation of serum of the patient in KBr density gradient according to (11).

Synthetic VLDL can be obtained by mechanical mixing (12) their key components, which are available as commercial products. While apolipoprotein E, phospholipids and cholesterol should be used in proportions corresponding to their content in native VLDL plasma (13).

As physiologically acceptable solvent used saline solution, water for injection or buffer solutions, for example phosphate-saline buffer pH 7.4 composition: KH2PO4- 231 mg %, Na2HPO4- 738 mg %, NaCl - 877 mg %.

In vivo means is about intended for intravenous or intraperitoneal administration.

Apoptosis is a natural mechanism of death of any of the cells is not accompanied by the development of inflammatory processes and does not lead to complications (14).

It is known that cortisol relates to inducers of apoptosis in animal cells (11), and very low density lipoproteins (VLDL) rich sphingomyelin, which in sphingomyelinase the cell cycle turns into ceramide - inducer of apoptosis (11, 14). In addition, the protein component of VLDL - apoE inhibits protein synthesis in tumor cells (15, 16). However, each of these components funds separately does not provide an effective apoptosis of tumor cells. Found that when using the claimed ratio of components is formed complex glucocorticoid hormone with lipoprotein very low density, providing synergistic antitumor activity of the ligand (glucocorticoid hormone) and its vector (VLDL). Pre-emptive action funds on tumor cells is due to the fact that unlike normal cells, they are more actively seize the very low density lipoproteins (17). A wide range of funds on tumors of different localization is provided by the participation of glucocorticoid hormones in the metabolism of cells of various organs and tissues is the presence of cellular receptors (18).

The effectiveness of the funds has been evaluated in in vitro experiments on cell cultures of ascitic hepatoma-1 obtained in the induction of mice male line of A/Sn o-aminoazotoluene (vivarium of the Institute of Cytology and genetics SB RAS, Novosibirsk). In the experiments used cells isolated on the ninth day after perelivania them into the abdominal cavity of mice of the same line rate of 1 million cells per individual. In this work, we used mice of ICR with ascitic Ehrlich carcinoma (vivarium of the Institute of Cytology and genetics SB RAS). Cells of peritoneal exudate received on the tenth day after the passage of the tumor for further cultivation. In mice with ascitic ON-1 hepatoma, and with ascitic Ehrlich carcinoma resulting from the introduction of funds received decrease in the population of tumor cells, as well as a decrease in the volume of ascitic fluid, which is formed by the progressive development of the tumor. Morphologically detected the full picture apoptosis of tumor cells, including the sequestration of cytoplasm, fragmentation of nuclei, the suppression of the synthesis of nucleic acids and protein.

The invention is illustrated in the following graphics:

Fig.1. The ascitic cells ON-1 hepatoma with tumor-associated macrophages. Painting by Romanovsky-Institute (HC. ×400).

Fig.2. Electrophoresis is NC agarose gel. Tracks: (1) control; (2) - VLDL; (3) is declared the tool part 3.

Fig.3. Electron microscopy of cells of ascitic Ehrlich carcinoma, ×8000. The action of the stated means of composition 3 (1 - a ruined cell, 2 - cell in a state of apoptosis), ×8000.

Fig.4. Electron microscopy of cells of ascitic Ehrlich carcinoma after intra-peritoneal injection. And Control (injection of physiologic saline), ×1000; B - the claimed means of composition 5 (×8000).

Fig.5. Mouse strain ICR on the 12th day after perelivania ascitic Ehrlich carcinoma. And Control (physiologic solution); B - the Experience (the claimed tool part 5)

Examples of specific performance

Example 1. Cytotoxic activity funds in the culture of ascitic cells ON-1 hepatoma mice (tumor cells of the liver), incubated together with tumor-associated macrophages.

Joint culture of ascitic cells ON-1 hepatoma mice and tumor-associated macrophages used in order to bring the conditions of the experiment to the holistic organism, because it is known that macrophages organism actively interact with tumor cells.

The very low density lipoproteins were obtained from the blood plasma of experimental Wistar rats. The secretion of lipoproteins from blood plasma of rats was performed isoproterenol of ultracentrifugation in KBr solutions in the presence of 3 m the EDTA-Na 2in the centrifuge "Optima L-90 K, Beckman-Coulter (Austria) using a rotor 70.1 Ti. Received a fraction of the very low density lipoproteins (VLDL, 0.94<d<1.006 g/ml). Obtained in this method VLDL were dialyzed for 24 hours at 4°C against 0.05 M potassium phosphate buffer pH 7.4, containing 0.15 M NaCl and 0.3 mm EDTA - Na2, further sterilized by filtration through "Milliporell" (USA) with a pore diameter of 22 μm and used within one week. Analysis of the purity of lipoproteins was performed using disc electrophoresis in polyacrylamide gel with sodium dodecyl sulfate ("Serva, Germany).

For the formation of tumors the mice A/Sn intraperitoneally transplanted cells ascitic ON-1 hepatoma based 1.0 million cells per mouse. Cells of peritoneal exudate received on the tenth day after the passage of the tumor for further cultivation. Freshly isolated tumor cells resuspendable in medium RPMI-1640 with L-glutamine containing 20 mm HEPES/NaOH (pH of 7.4), 2 mm L-glutathione, 100 u/ml penicillin, 50 μg/ml gentamicin, 5.6 mM glucose and 10 nm insulin. Incubation was carried out at 37°C in an atmosphere of 5% CO2and 95% air at a humidity of 85%. The final density of tumor cells was 5×106mm2. The incubation period of 24 hours. The proliferative activity of tumor cells was estimated by the rate include3H-thymidine into DNA. The protein content in the samples ODA is delali by the method of Warburg Christian (19).

To assess the antitumor effect on the culture of tumor cells in the ascitic ON-1 hepatoma in vitro used the claimed means of two compositions.

The claimed means of structure 1, including cortisol (40 mg %), very low density lipoproteins in an amount to provide the content of apolipoprotein E in the formula 1 mg %; saline solution. The claimed means of composition 1 was injected into the culture of cells in a volume of 200 µl per ml of incubation medium.

The claimed means of part 2, including corticosterone (0.3 µg %), very low density lipoproteins in an amount to provide the content of apolipoprotein E in the formula 1 mg %; phosphate-saline buffer. The claimed means of composition 2 was injected into the culture of cells in a volume of 200 µl per ml of incubation medium.

The ascitic cells ON-1 hepatoma with tumor-associated macrophages is shown in Fig.1. In mice (in vivo) they are actively dividing, so that the life expectancy of animals does not exceed 2-3 weeks. Culture of these cells without adding funds were used as control.

It is shown that the claimed means of structure 1 inhibits the proliferation of tumor cells, as evidenced by the decrease in the rate of biosynthesis of DNA in 2 times in comparison with control (Table.1), while the effect of the stated means of composition 1 boliviarian, than the effect of each of its active components separately.

Similar results were obtained when using the claimed means of composition 2 (table 2).

Table 1.
Changing the speed of the biosynthesis of DNA in coculture cells-1 hepatoma under the influence of the stated means of structure 1 in comparison with the effect of its active components
Conditions of incubationPulse/min/mg protein M±m, n=6
Control14233±1802
VLDL9647±1613
Cortisol9903±2644
The claimed tool part 16909±565*
* - significant difference compared to controls (p<0,01)

Table 2.
Changing the speed of the biosynthesis of DNA in coculture cells-1 hepatoma under the influence of the stated means of composition 2 in comparison with the effect of its active components on individual p is STI
Conditions of incubationPulse/min/mg protein M±m, n=6
Control12681±420
VLDL8113±1698
Cortisol10286±1671
The claimed tool part 27927±1671*
* - significant difference compared to controls (p<0,05)

The analysis of the binding of VLDL with cortisol in the composition of the claimed anti-cancer drugs have shown that it varies within 12-18% of the total content of cortisol; the binding of corticosterone with VLDL varies in the range of 8-16%. This is a very high figures. The binding constant for cortisol is (5±0,1)·106M-1for corticosterone (8±0,1)·106M-1. The data obtained show that the complex formation of each of these hormones with VLDL in the composition of the claimed anti-cancer drugs provides the synergy of their actions on the rate of biosynthesis of DNA in the culture of tumor cells

Example 2. Cytostatic effect of the claimed anti-cancer agents in cell cultures of ascitic Ehrlich carcinoma.

Ascitic Ehrlich carcinoma is the Wallpaper spontaneous carcinoma of the mammary gland of mice.

The ICR mice intraperitoneally transplanted cells ascitic Ehrlich carcinoma based 3.0 million cells per mouse. Cells of peritoneal exudate received on the tenth day after the passage of the tumor for further cultivation. Freshly isolated cells resuspendable in medium RPMI-1640 with L-glutamine containing 20 mm HEPES/NaOH (pH of 7.4), 2 mm L-glutathione, 100 u/ml penicillin, 50 μg/ml gentamicin, 5.6 mM glucose and 10 nm insulin. Incubation was carried out at 37°C in an atmosphere of 5% CO2and 95% air at a humidity of 85%. The final cell density of 5×106mm2. The incubation period of 24 hours. Proliferative activity of the cells was estimated by the rate include3H-thymidine into DNA.

To assess the antitumor effect on the culture of tumor cells in the ascitic Ehrlich carcinoma in vitro used the claimed means of two compositions.

The claimed means of part 3, including targetrotation (31,4 µg %), very low density lipoproteins in an amount to provide the content of apolipoprotein E in the formula 1 mg%; saline buffer solution. The claimed means 3 was injected into the culture of cells in a volume of 200 µl per ml of incubation medium.

The claimed means of part 4, including cortisol (0.3 µg %), very low density lipoproteins in an amount to provide content apolipoprotein is E in tool 1 mg %; saline solution. The claimed means of composition 4 was injected into the culture of cells in a volume of 200 µl per ml of incubation medium.

It is shown that the claimed composition tool 3 speed was reduced biosynthesis of DNA in the tumor cells of ascitic Ehrlich carcinoma 1.7 times (Table.3), the effect of its active components was not significantly different from the control.

Similar results were obtained when evaluating the cytotoxic actions stated antineoplastic composition 4 (table 4).

Table 3.
Changing the speed of the biosynthesis of DNA in coculture cells of ascitic Ehrlich carcinoma under the influence of the claimed anti-cancer drugs 3 in comparison with the effect of its active components
Conditions of incubationPulse/min/mg protein M±m, n=6
Control7805±447
VLDL5002±298
Tetrahydrocortisol5939±236
The claimed composition tool 34176±376*
* reliable RA is lichev compared to controls (p< 0,05)

Table 4.
Changing the speed of the biosynthesis of DNA in coculture cells of ascitic Ehrlich carcinoma under the influence of the claimed anti-cancer drugs 4 in comparison with the effect of its active components
Conditions of incubationPulse/min/mg protein M±m, n=6
Control4304±473
VLDL1892±427
Cortisol223U611
The claimed composition tool 41382±144*
* - significant difference compared to controls (p<0,05)

Presents data similar to those obtained on cells from ascitic ON-1 hepatoma, and confirm that the antitumor activity of the claimed anti-cancer drugs on the culture of tumor cells appears in the above range (0.3 ág % - 40 µg %) of the equity content of the hormone from the group of glucocorticoids (cortisol and its derivatives) in its composition.

Data electrophoretic analysis of DNA samples tile is to ascitic Ehrlich carcinoma confirm the results by the inclusion of 3H-thymidine (Fig.2). A significant decrease in the DNA content in samples of the culture of tumor cells indicates a sharp decrease in proliferation and cell death ascitic Ehrlich carcinoma.

Electron microscopic analysis of changes in the structure of the cells showed loss of microvision, the sequestration of cytoplasm in the incubation medium and fragmentation of nuclei (Fig.3). There is a fragmentation of the nuclei, the appearance in the structure of apoptotic cells. Signs allow us to classify the mechanism of tumor cell death under the influence of the claimed anti-cancer drugs to apoptosis. Absence of effect of suppression of the proliferative activity of tumor cells under the influence of VLDL or cortisol separately indicates a cooperative mechanism of action of these components in the tool, i.e. the synergy of their actions.

Example 3. Cytostatic effect of the claimed anti-cancer agents in cells of ascitic Ehrlich carcinoma in vivo.

The ICR mice intraperitoneally transplanted cells ascitic Ehrlich carcinoma based 3.0 million cells per mouse. After 10 days began to enter VLDL or declared antitumor agent composition 5: cortisol in the amount of 40 mg %, VLDL - in an amount to provide the content of apolipoprotein E in the formula 2 mg %; saline solution. The claimed tool (experience) or saline (control) was injected into mice intraperitoneally or intravenously in a volume of 0.02 ml per 1 g of the weight of the animal.

One group of mice, the drug was injected intravenously, and the other intraperitoneally. Did 3 injections within 8-9 days. Then, animals were scored gentle way under light sedation. Measured total volume of ascitic fluid in the abdominal cavity, which is a measure of the extent (stage) of development of tumor, and the number of tumor cells with the camera Goryaeva.

Received tumor cells were incubated in vitro in the presence of14C-leucine at a dose of 2 µci/ml incubation period is 24 hours. Radioactivity was expressed in counts/min per mg protein. It was found that in the control volume of ascitic fluid per animal averaged 11 ml with a total content of tumor cells per animal 600 million; in the experimental group and 5.7 ml of ascitic fluid and 300 million tumor cells, respectively. At the same time declared the tool part 5 significantly (54%) inhibited the rate of protein synthesis in the General culture of tumor cells in vitro. VLDL separately, on the contrary, increased the rate of protein synthesis, due to the increased capture and use of VLDL tumor cells as a building material (PL.5, 6).

As is eduit from tables 5 and 6, intravenous stated antineoplastic somewhat less effective than intraperitoneal administration, judging by the speed include14C-leucine into protein. However, a comparison of the volume of ascitic fluid (3 ml) and number in it cells (300 million cells) allows us to conclude that the inhibitory effect funds on the growth of tumor cells is quite pronounced and when administered intravenously.

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Table 5.
The rate of biosynthesis of protein in the total cell culture of ascitic Ehrlich carcinoma intraperitoneal injection of declared antineoplastic composition 5
Conditions of incubationPulse/min/mg protein M±m, n=6
Control99254±1577
VLDL131277±3772#
The claimed tool part 545424±1578∗
∗ - significant difference compared to controls (p<0,001)
#- no significant difference compared with the complex cortisol-VLDL (p<0,001)

Table 6.
The rate of biosynthesis of protein in the total cell culture of ascitic Ehrlich carcinoma intravenous stated antineoplastic composition 5
Conditions of incubationPulse/min/mg protein M±m, n=6
Control103726±4163
The claimed tool part 580750±3614∗
∗ - significant difference compared to controls (p<0,05)

Morphological analysis of the characteristics of apoptosis of tumor cells under the influence of the claimed anti-cancer agents in experiments revealed a number of major morphological features of apoptosis of tumor cells: the fragmentation of the nucleus, loss of microvision cells and cytoplasmic sequestration formations in the incubation medium (Fig.4).

Mice treated with antitumor agent, was significantly different from untreated: treated mice had more healthy, consume more food and after three injections of funds didn't contain the ascitic fluid (Fig.5).

Thus, n the mice with ascitic ON-1 hepatoma, and with Ehrlich carcinoma resulting from the introduction of the claimed anti-cancer agents obtained a reduction in the population of tumor cells, as well as a decrease in the volume of ascitic fluid. Morphologically detected the full picture apoptosis of tumor cells, including the sequestration of cytoplasm, fragmentation of nuclei, the suppression of the synthesis of nucleic acids and protein.

List of used sources

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4. De Smidt P. S., van Berkel, T. J. Characteristics of association of oleoyl derivatives of 5-fluorodeoxyuridine and methotrexate with low-density lipoproteins (LDL) // Pharm Res. 1992. 9(4). P. 565-569.

5. Rodrigues D. G., Covolan C. C., Coradi S. T., R. Barboza, R. C. Maranhão Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel // J. Pharm. Pharmacol. 2002. 54(6). P. 765-772.

6. Pires LA, Hegg R, Valduga CJ, Graziani SR, Rodrigues DG, Maranhão RC. Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study // Cancer Chemother Pharmacol. 2009. 63(2):281-7. doi:10.1007/s00280-008-0738-2. Epub 2008.

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1. Antitumor agent, including hormone and very low density lipoproteins, characterized in that for suppression of tumor growth by triggering apoptosis of tumor cells it includes glucocorticoid hormone in the amount of 0.3 μg % - 40 mg %, very low density lipoproteins in an amount to provide the content of apolipoprotein E in the formula and not less than 1 mg %; the tool further includes a physiologically acceptable solvent.

2. Means under item 1, characterized in that as it includes glucocorticoids cortisol or its analogs.



 

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5 cl, 45 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.

EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.

27 cl, 1 tbl, 5 dwg, 25 ex

FIELD: medicine.

SUBSTANCE: treating locally advanced oropharyngeal cancer is ensured by a radiation therapy in the mode of dynamic dose fractionation. The radiation therapy is started by supplying a fraction dose of 2.4 Gy. After 2 days of treatment gap, the patient is exposed to total fractions at a fraction dose of 3.6Gy for three days. Each session is precede by placing high-structure hydrogel matrix of sodium alginate under a patient's tongue with metronidazole 150mg and bilberry 20-35mg pre-introduced into the matrix, for 4-5 hours twice every 1-2 hours. The two following sessions of the exposure at a fraction dose of 2.4 Gy are preceded by placing the matrix once under the tongue for 4-5 hours. After 2 days of treatment gap, the following 5 sessions of the radiation therapy are performed at a fraction dose of 2.4 Gy to a cumulative dose of 30Gy. Colegel-DNA-Ch high-structure disk is preliminary placed under the tongue for 4-5 hours.

EFFECT: method enables avoiding the compulsory gaps of the radiation therapy by reducing a rate of severe local radiation reactions, and provides the target delivery and accurate dosage of metronidazole administered into the patient's body leading to the partial death of well-oxygenated cells and re-oxygenation of hypoxic tumour cells.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a pharmaceutical composition for treating Parkinson's disease, containing a pharmaceutically acceptable carrier and a combination of flat doses of controlled release pramipexole and controlled release rasagiline; the above combination of flat doses contains pramipexole in an amount of 0.06 mg to less than 1.5 mg and rasagiline in an amount of 0.05 mg to less than 1.0 mg.

EFFECT: invention provides the synergetic action of rasagiline and pramipexole in treating Parkinson's disease.

3 cl, 11 dwg, 3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: as an active substance, the composition contains butoconazol, a base that is a combination of a hydrophobic ingredient, a hydrophilic ingredient and an emulsifier, and also a gel-forming polymer. Hydroxypropylstarch phosphate is preferentially used as the gel-forming polymer. A method for preparing the declared composition consists in the fact that a mixture of butoconazol with a portion of the hydrophilic ingredient, the hydrophobic ingredient and emulsifier is added with a dispersion of the gel-forming polymer in the rest of the hydrophilic ingredient; the produced mixture is agitated homogenously with a preserving agent added where it might be necessary.

EFFECT: new pharmaceutical composition is characterised by a high level of antifungal activity, stability both at a storage temperature, and at a use temperature, and good pack extrusion.

14 cl, 2 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition contains recombinant interferon specified in a group: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, metronidazole, hypromellose, antiseptics and a consistency base in the following relation of ingredients, g per 1 ml of the mixture: recombinant interferon, IU 100-10,000,000; metronidazole 0.00001-0.5; hypromellose 0.00001-0.5; antiseptics 0.00001-0.5; consistency base - the rest. Besides, the pharmaceutical composition contains antibiotics specified in a group: baneocin, levomycin, tetracycline, amoxicilline in an amount of 0.00001-0.5 g. Besides, the pharmaceutical composition contains antiseptics specified in a group: boric acid, salicylic acid, hydrogen peroxide, chlorhexidine, ethanol, povidone iodine, silver nitrate, silver sulphadiazine in an amount of 0.00001-0.5 g. Besides, the pharmaceutical composition contains anesthesin or lidocaine as local anaesthetics in an amount of 0.00001-0.5 g. Besides, the pharmaceutical composition contains vitamin A or beta-carotene as food colorants in an amount of 0.00001-0.5 g. Besides, the pharmaceutical composition contains flavouring agents specified in a group of: tea tree oil, menthol oil, eucalyptus leaf oil in an amount of 0.00001-0.5 g. Besides, the pharmaceutical composition contains macrogol 400, or macrogol 1500, or macrogol 4000 as a consistency base.

EFFECT: more effective treatment.

7 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a pharmaceutical composition used for treating or preventing a cardiovascular disease in an individual in need thereof and containing at least 95% ethyleicosapentaenoate (ethyl-EPA) encased in a capsule containing gelatine, glycerol, sorbitol, maltitol and purified water, wherein the composition has an initial peroxide number of no more than 5 mEq/kg and the second peroxide number of no more than 8 mEq/kg if stored at 25°C and relative humidity (RH) of 60% for 6 months.

EFFECT: invention refers to a method of treating or preventing the cardiovascular diseases involving administering a therapeutically effective amount of this composition into the individual in need thereof.

18 cl, 4 ex, 4 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: composition contains tacrolimus as an active substance in a therapeutically effective amount, a hydrophobic ingredient, a hydrophilic ingredient, an emulsifier and a stabiliser - disodium edentate and phenoxyethanol. As tacrolimus, the composition contains tacrolimus monohydrate. The composition contains phenoxyethanol in a combination with ethylhexyl glycerol in a ratio of 9:1. The composition is presented in the form of a semi-solid dosage form.

EFFECT: formulation is characterised by stability, uniform distribution of the active substance, usability and good pack extrusion.

6 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains aleglitezar or its sodium salt in a dose of 0.01 to 0.9 mg.

EFFECT: pharmaceutical composition of aleglitezar is used for treating or preventing type II diabetes mellitus or cardiovascular diseases.

32 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, namely to manufacturing drug preparations for treating allergic diseases, such as allergic rhinitis and urticaria. According to the first version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including citric acid, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, lactose, magnesium stearate, and talc. According to the second version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including Pearlitol 100SD-Mannitol, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, magnesium stearate, and talc. According to the third version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, colloidal silicone dioxide, and sodium sodium stearyl fumarate. According to the fourth version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, Pearlitol 100SD-Mannitol, magnesium stearate, and talc. The pharmaceutical composition is presented in the form of a film-coated tablet.

EFFECT: pharmaceutical composition according to the invention is storage-stable and releases the active substance quickly in the gastrointestinal tract.

10 cl, 9 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claim describes a standard solid dosage form for oral administration which represents a mini-tablet having a core and an outer coating, wherein the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, while the outer coating represents a film coating containing a taste masking material specified in polyacrylates, and/or a release modifying ingredient of the coating specified in cellulose derivatives and acryl copolymers, and a mixture thereof. The above mini-tablet has a size of 1 mm to 4 mm and contains aliskiren in an amount making 2 mg/tablet to 4 mg/tablet. The oral solid dosage form is preferentially applied in paediatrics.

EFFECT: according to the invention, the dosage form of aliskiren can be dosed and possesses a taste that makes it applicable for children, and maintains a biological availability at a level comparable to that of the available medicinal product for adults.

19 cl, 13 dwg, 5 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions based on botulinum toxin and is intended for diagnostic or therapeutic introduction to a subject. A lyophilised or dried in vacuum composition contains botulinum toxin, stabilised with a non-protein excipient; a compound, selected from the group, consisting of the first monosaccharide, the first disaccharide, the first trisaccharide and the first alcohol, obtained by the reduction of the first monosaccharide; and a compound, selected from the group, consisting of the second monosaccharide, the second disaccharide, the second trisaccharide, the second alcohol and amino acid. In the other aspect the pharmaceutical composition contains botulinum toxin, stabilised with the non-protein excipient; polyethyleneglycol and a compound, selected from the group, consisting of monosaccharide, disaccharide, trisaccharide and amino acid. The pharmaceutical composition can contain botulinum toxin, stabilised with the non-protein excipient, polyvinylpyrrolidone; and disaccharide. The pharmaceutical composition of botulinum toxin, which does not contain an animal protein, includes botulinum toxin; a compound, selected from the group, consisting of the first monosaccharide, the first disaccharide, the first trisaccharide and amino acid.

EFFECT: application of the group of inventions provides the stable pharmaceutical composition for diagnostic or therapeutic introduction to a subject.

6 cl, 8 tbl, 5 ex

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

FIELD: biotechnologies.

SUBSTANCE: peptide is characterised with sequence Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ ID NO: 16). The invention also relates to peptide/lipid complex based on the above peptide, in which phospholipid represents one or more of sphingomyelin, DPPC and DPPG, a pharmaceutical composition that contains it, and treatment methods of dyslipidemia, cardiovascular disease, endothelial malfunction, macrovascular illnesses and microvascular illnesses using it.

EFFECT: invention allows obtaining ApoA-I mimetic that is more stable in comparison to ApoA-I and that is easy to obtain.

14 cl, 21 dwg, 14 tbl, 24 ex

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