RU2362579C1 - Pharmaceutical composition on basis of peptide possessing antitumoral action - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: composition contains a peptide possessing antitumoral action, and can be used in clinical practice for treatment of tumours. The pharmaceutical composition and an agent possessing antitumoral action, contain effective quantity of a peptide of formula H-Glu-Asp-Gly-OH in quality of operating substance and a pharmaceutically comprehensible carrier. Thus the pharmaceutical composition is in the form suitable for parenteral introduction.

EFFECT: antitumoral action at the expense of inhibition of proliferative activity of tumoral cells.

3 cl, 3 ex, 2 tbl

Description

The invention relates to medicines used in clinical oncology, and relates to a pharmaceutical composition containing a peptide having an antitumor effect, which can be used in clinical practice for the treatment of tumors.

Modern medicine has a fairly extensive arsenal of drugs for the treatment of cancer patients. It is known to use a drug based on a cyclic octapeptide manufactured by the Sandos company in the clinical treatment of tumor tumors (N.F. Orel et al., Modern Oncology, vol. 2, No. 1, 2000).

In clinical practice, cytostatics are also widely used: sarcolysin, cyclophosphamide and cisplatin (Mashkovsky MD Medicines. T.2. Kharkov: Torsing, 1997. S.437, 439, 458). It is important to note that when using this group of drugs, serious side effects are possible: impaired renal function, nausea, vomiting, loss of appetite, dizziness, tinnitus, hearing loss, anaphylactic reactions, leukopenia, thrombocytopenia, anemia, neuropathy with primary damage to the nerves of the lower extremities . In this regard, there are a significant number of contraindications to the use of this group of drugs: impaired renal and hepatic function, inhibition of bone marrow hematopoiesis, circulatory disorders, gastric and duodenal ulcer, pregnancy.

Nevertheless, in oncology, an active search is underway for antitumor drugs of a peptide nature that exhibit high specific activity and at the same time do not have serious contraindications and side effects.

The prior art means of peptide nature with antitumor activity.

Known pentapeptide with antitumor activity M ₂ Val-Mval-Pro-Pro-NH-Bzl HCl (patent RU No. 2153504, 1995). Known antitumor agent, which is a non-toxic hexapeptide of the formula Leu-Val-Val-Tyr-Pro-Trr (patent RU 2067870, 1993). The use of the peptide H-Lys-Gln-OH is known to inhibit the growth of tumor cells (WO 86/04334 A1, publ. 31.07.1986). Known pharmaceutical composition using new derivatives of peptides that have tumor inhibitory activity (patent RU 2116312, 1998).

Despite the fact that the known peptide agents provide potentially improved therapeutic possibilities for the medical treatment of tumors, the development of new peptide agents remains relevant.

The glutamyl-aspartyl-glycine peptide of the general formula: H-Glu-Asp-Gly-OH (Registration Number RN-75007-24-8 according to STN int. BD Registry Chemical abstract) is known in the art.

It is also known that the peptide H-Glu-Asp-Gly-OH has a stress-protective effect (patent RU No. 2304444, 2006).

In an experimental study of the glutamyl-aspartyl-glycine peptide of the general formula: H-Glu-Asp-Gly-OH, its previously unknown property was revealed, which manifests itself in the antitumor effect.

The present invention posed and solved the problem of obtaining funds of a peptide nature with antitumor activity.

The technical result of the invention consists in the manifestation of a glutamyl-aspartyl-glycine peptide of the formula: H-Glu-Asp-Gly-OH with an antitumor effect, the use of which as an active substance in a pharmaceutical composition for oncological diseases has an antitumor effect due to inhibition of the proliferative activity of tumor cells.

To solve the problem and achieve the technical result, a group of inventions is proposed, united by a common inventive concept.

In one of its aspects, the present invention relates to a pharmaceutical composition having an antitumor effect, containing as an active substance an effective amount of a glutamyl-aspartyl-glycine peptide of the formula: H-Glu-Asp-Gly-OH and a pharmaceutically acceptable carrier.

In this case, the pharmaceutical composition is in a form suitable for parenteral administration.

In another aspect, the present invention relates to an antitumor agent comprising, as an active ingredient, an effective amount of a glutamyl-aspartyl-glycine peptide of the formula: H-Glu-Asp-Gly-OH and a pharmaceutically acceptable carrier.

Glutamyl-aspartyl-glycine peptide of the formula: H-Glu-Asp-Gly-OH is obtained by the classical method of peptide synthesis in solution.

An experimental study of the glutamyl-aspartyl-glycine peptide of the formula: H-Glu-Asp-Gly-OH revealed that it exhibits a new biological activity, which is manifested in the antitumor effect.

The possibility of an objective manifestation of a technical result when using the invention is confirmed by reliable data containing experimental information obtained by methods adopted in this field.

The study of biological activity was carried out on animals in an experimental model of Ehrlich cancer using a strain of transplantable tumors of mice of the SHR line.

The term "pharmaceutical composition" refers to various dosage forms containing a peptide that can find therapeutic use in medicine as an agent with an antitumor effect.

To obtain the pharmaceutical compositions of the invention, an effective amount of the H-Glu-Asp-Gly-OH peptide as an active ingredient is mixed with a pharmaceutically acceptable carrier according to pharmaceutically acceptable compounding methods.

The term "effective amount" means the use of such an amount of active substance, which, in accordance with its quantitative indicators of activity and toxicity, as well as on the basis of specialist knowledge should be effective in this dosage form.

As a carrier, various substances may be used depending on the dosage form of the preparation desired for administration to the body. For parenteral administration, saline or sterile water is usually used as a carrier.

The invention is illustrated in tables.

Table 1 shows the effect of a pharmaceutical composition containing the active ingredient H-Glu-Asp-Gly-OH peptide on tumor growth in an experimental model of Ehrlich cancer in SHR mice.

Table 2 shows the effect of the peptide H-Glu-Asp-Gly-OH, used as an active substance in the pharmaceutical composition, on the morphological and biochemical parameters of the peripheral blood of guinea pigs in the study of chronic toxicity.

The invention is illustrated by an example of the synthesis of a glutamyl-aspartyl-glycine peptide of the general formula: H-Glu-Asp-Gly-OH (Example 1), an example confirming the antitumor effect of a pharmaceutical composition containing, as an active ingredient, an H-Glu-Asp-Gly-OH peptide (example 2), as well as an example of studying the toxicity of the peptide H-Glu-Asp-Gly-OH, used as an active substance in the pharmaceutical composition (example 3).

Example 1. The synthesis of the peptide H-Glu-Asp-Gly-OH

1. Name of the compound: glutamyl-aspartyl-glycine.

2. Structural formula H-Glu-Asp-Gly-OH

3. Gross formula without counterion: C ₁₁ H ₁₇ N ₃ O ₈ .

4. Molecular weight without counterion: 319.27.

5. Counterion: acetate.

6. Appearance: odorless white amorphous powder.

7. Synthesis method: the peptide is obtained by the classical method of synthesis in solution according to the scheme:

BOC - tert-butyloxycarbonyl group,

OSu - N-oxysuccinimide ester,

DCC - N, N'-Dicyclohexylcarbodiimide,

OBzl - benzyl ether,

TFA - trifluoroacetic acid,

HOBt - N-hydroxybenzotriazole.

Characteristics of the finished product:

the content of the main substance: 97.93% (by HPLC, 220 nm),

- TLC - individual, R _f = 0.45 (acetonitrile-water 1: 2),

- moisture content: 6%,

- pH 0.01% solution: 4.9,

- specific optical rotation: [α] _D ²² : -31 ° (c = 1, H ₂ O), "Polamat A", Carl Zeiss Jena.

Synthesis Example:

1) BOC-Glu (OBzl) -OSu, N-tert-butyloxycarbonyl- (γ-benzyl) glutamic acid N-oxysuccinimide ester (I).

N-tert-butyloxycarbonyl- (γ-benzyl) glutamic acid BOC-Glu (OBzl) -OH (33.7 g, 0.1 mol) was dissolved in 50 ml of N, N'-dimethylformamide, cooled to a temperature of -10 ° С , cooled (4-6 ° C) solutions of N, N'-dicyclohexylcarbodiimide (23.0 g, 0.11 mol) in 30 ml of N, N'-dimethylformamide and N-hydroxysuccinimide (13.0 g, 0) were added with stirring , 11 mol) in 20 ml of N, N'-dimethylformamide. The reaction mixture was stirred for 12 hours while cooling with ice and then for 1 day at room temperature. The precipitated N, N'-dicyclohexylurea was filtered off and the resulting activated ester solution was used without isolation in the next step.

2) BOC-Glu (OBzl) -Asp (OBzl) -OH, N-t-butyloxycarbonyl- (γ-benzyl) glutamyl- (β-benzyl) aspartate (II).

(β-Benzyl) aspartic acid H-Asp (OBzl) -OH (28.0 g, 0.12 mol) and 36 ml (0.12 mol) of triethylamine were suspended in 50 ml of N, N'-dimethylformamide and stirred for 1 h. Then, a solution of activated BOC-Glu (OBzl) -OSu (I) ester obtained in the previous step was added in portions. The reaction mixture was stirred at room temperature for 2 days. Then it was acidified with 0.5 N sulfuric acid to pH 2-3 and extracted with ethyl acetate 4x50 ml. The extracts were combined and washed successively with 0.5 n H ₂ SO ₄ 3 × 50 ml, water 2 × 50 ml, 5% NaHCO ₃ 2 × 50 ml, water 2 × 50 ml, saturated NaCl 2 × 50 ml. The organic layer was dried over Na ₂ SO ₄ , the solvent was evaporated in vacuo, the residue was crystallized under hexane. Received 50 g of the product (92%). R _f = 0.34 (benzene-acetone 2: 1).

3) BOC-Glu (OBzl) -Asp (OBzl) -Gly-OBzl (III), N-tert-butyloxycarbonyl- (γ-benzyl) glutamyl- (β-benzyl) aspartyl-glycine (III) benzyl ester.

2.7 g (5 mmol) of the dipeptide and 0.95 g (7 mmol) of oxybenzotriazole were dissolved in tetrahydrofuran (10 ml) and cooled to a temperature of -10 ° C. 1.44 g (7 mmol) of dicyclohexylcarbodiimide were dissolved in 5 ml of tetrahydrofuran and cooled to the same temperature. 3.4 g (10 mmol) of glycine benzyl ester tosylate was dissolved in 10 ml of tetrahydrofuran, 1.4 ml (10 mmol) of triethylamine was added and cooled to the same temperature. While cooling in an ice bath and vigorous stirring, the solutions of the dipeptide with oxybenzotriazole and carbodiimide were combined, and after 10 minutes a solution of glycine benzyl ester tosylate was added. The reaction mixture was stirred for 3 hours while cooling with ice and for 1 day at room temperature. The precipitated dicyclohexylurea was filtered off, the filtrate was evaporated in vacuo, the residue was dissolved in ethyl acetate (100 ml). The solution was washed sequentially with 0.5 N sulfuric acid, water, 5% sodium bicarbonate solution, water, dried over anhydrous sodium sulfate. Ethyl acetate was evaporated in vacuo, crystallization of the residue in ethyl acetate / hexane. Recrystallization from isopropanol. 2.74 g of product (85%) was obtained after drying in vacuo. R _f = 0.78 (benzene-acetone 1: 1).

4) H-Glu-Asp-Gly-OH (IV), glutamyl-aspartyl-glycine.

The protected tripeptide BOC-Glu (OBzl) -Asp (OBzl) -Gly-OBzl (III) (2.7 g) was dissolved in a mixture of methyl alcohol - water (4: 1) (50 ml) and hydrogenated over a Pd / C catalyst ( 5%) for 4 hours. The catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was dried in vacuo over KOH and P ₂ O ₅ . Then the product was dissolved in 15 ml of a mixture of methylene chloride-trifluoroacetic acid (5: 1) and kept at room temperature for 2 hours. The completeness of the release reaction was monitored by TLC in an acetonitrile-water system (1: 3). The solvent was evaporated in vacuo, the residue was dried in vacuo over KOH.

For purification, 300 mg of the preparation was dissolved in 4 ml of 0.01% trifluoroacetic acid and subjected to high performance liquid chromatography on a 50 × 250 mm reverse phase column Diasorb-130-C16T, 7 mkm. Chromatograph Beckman System Gold, 126 Solvent Module, 168 Diode Array Detector Module. Chromatography conditions A: 0.1% TFA; B: MeCN / 0.1% TFA, gradient B 0 → 50% in 100 min. Sample volume 5 ml, detection at 215 nm, scanning 190-600 nm, flow rate 10 ml / min. The main peak fraction was taken. The solvent was evaporated in vacuo at a temperature not exceeding 40 ° С, evaporation was repeated (5 times) with 10 ml of 10% acetic acid solution.

Finally, the residue was dissolved in 20 ml of deionized water and lyophilized. Received 150 mg of a purified preparation in the form of an odorless amorphous white powder.

5) Analysis of the finished product.

- The content of the basic substance was determined by HPLC on a Phenomenex C 18 LUNA column 4.6 × 150 mm. A: 0.1% TFA; B: MeCN; grad.B 0-100% in 10 min. Flow rate 1 ml / min. Detection at 220 nm, scanning 190-600 nm, sample 20µ1. The content of the main substance is 97.93%.

- TLC: individual, R _f = 0.45 (acetonitrile-water 1: 2, PTCX-P-B-UV Sorbfil plates, CTX-1VE silica gel 8-12 μm, manifestation of chlorine / benzidine).

- Moisture content: 6% (gravimetrically by weight loss during drying 20 mg at 100 ° C).

- pH 0.01% solution: 4.9 (potentiometric).

- Specific optical rotation: [α] _D ²² : -31 ° (c = 1, H ₂ O), "Polamat A", Carl Zeiss Jena.

Example 2. The study of the antitumor effect of a pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH

The antitumor effect of a pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH as an active ingredient was studied using a model of Ehrlich cancer, a strain of transplantable mouse tumors that is widely used for the selection and further study of anticancer agents.

Ehrlich cancer was inoculated with 80 female SHR mice under the skin of the right side in the amount of 107 cells in 0.1 ml of physiological saline.

48 hours after transplantation, the tumors of animals were randomly divided into 4 groups.

20 animals of the control group were subcutaneously injected with 0.2 ml of sterile saline solution 5 times a week for 1 month (20 injections in total).

Twenty animals of the experimental group I were injected with 0.1 μg per mouse, and 20 animals of the experimental group 2 - 2 μg per mouse of the peptide H-Glu-Asp-Gly-OH in 0.2 ml of sterile saline solution 5 times a week for 1 month (total 20 injections).

20 animals of the comparison group were once intraperitoneally injected with the conventional cytostatic drug cisplatin at a dose of 5 mg / kg, using it as a comparison drug.

Twice a week, the length and width of the tumor nodes were measured in animals. Tumor volume was calculated by the formula:

V = (a b2) / 2,

where a is the larger, a b is the smaller linear size of the node.

The effectiveness of therapy was evaluated by inhibition of tumor growth. The percentage inhibition of tumor growth was calculated by the formula:

(VK-VO) / VK100%,

where VK is the average tumor volume in animals of the control group, and VO is the average tumor volume in animals of the experimental group.

The results of a study of the effect of drugs on the growth of solid Ehrlich cancer are presented in Table 1.

From the data shown in Table 1, it follows that when introduced in the indicated doses and modes, the pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH at a dose of 0.1 μg / mouse in the early stages is statistically unreliable (with the exception of 18 days of tumor growth), a tendency to inhibit tumor growth, but in later stages is ineffective.

From the data shown in Table 1, it also follows that the introduction of a pharmaceutical composition at a dose of 2 μg / mouse statistically significantly inhibits the growth of Ehrlich cancer by 71%.

It is important to note that in this experiment, the comparison drug cisplatin is no more active than the pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH at a dose of 2 μg / mouse: cisplatin statistically significantly inhibits the growth of Ehrlich cancer by 60%.

Thus, as can be seen from the data presented in Table 1, the introduction of a pharmaceutical composition containing the active substance peptide H-Glu-Asp-Gly-OH at a dose of 2 μg / mouse, when administered subcutaneously, has a 20-fold anti-tumor effect, expressed in inhibition of Ehrlich tumor growth, comparable in effectiveness with the cytostatic drug cisplatin.

The results obtained during the studies also indicate the property of the pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH as an active substance, to exert an antitumor effect.

According to the invention, the pharmaceutical composition, administered at the indicated doses to the animals, provides an antitumor effect. In this case, the dose may vary depending on the nature and severity of the disease, the weight of the patient, concomitant treatment and other factors known to specialists.

However, in general, a pharmaceutical composition containing the active substance H-Glu-Asp-Gly-OH peptide according to the present invention can be administered in an amount of 100 μg / kg body weight of a patient (animal or human) in a single dose . The preferred dose for one patient in need of such treatment is in the range from 1 to 10 mg per day, and the preferred course of treatment is from 10 to 20 days.

In order to confirm the absence of toxicity of the peptide H-Glu-Asp-Gly-OH at the indicated doses of administration, Example 3 is given below.

Example 3. The study of the toxicity of the peptide H-Glu-Asp-Gly-OH

The general toxic effect of the peptide H-Glu-Asp-Gly-OH, used as an active substance in the pharmaceutical composition, was studied in accordance with the requirements of the Guidelines for the experimental (preclinical) study of new pharmacological substances (2000): acute toxicity with a single injection of the drug, as well as subacute and chronic toxicity with prolonged administration of the peptide.

A study of acute toxicity was conducted on 66 outbred white male mice weighing 20-22 g. Animals were randomly divided into 6 equal groups. The drug was administered to animals once intramuscularly at doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg in 0.25 ml of sterile 0.9% NaCl solution. Animals of the control group were injected with the same volume of 0.9% NaCl solution.

Studies on the study of subacute toxicity were carried out on 64 white mongrel male rats weighing 180-220 g. Once daily, the animals of the experimental groups were injected intramuscularly for 90 days at doses of 1 μg / kg, 0.1 mg / kg, 1 mg / kg 0.5 ml of a sterile 0.9% NaCl solution. The animals of the control group were injected in the same volume with a sterile 0.9% NaCl solution. Before administration of the drug, on the 30, 60 and 90 days after the start of drug administration, the morphological composition and properties of peripheral blood were studied in animals. At the end of the experiment, biochemical and coagulological blood parameters were examined.

Studies of chronic toxicity were carried out for 6 months, based on the duration of the recommended clinical prescription of the drug, in 92 male guinea pigs weighing 310-350 g. Animals of the experimental groups received daily once intramuscularly a peptide for 6 months at doses of 1 μg / kg, 0.1 mg / kg, 1 mg / kg in 0.5 ml of a sterile 0.9% NaCl solution. In the control group, animals were injected in a similar fashion with a sterile 0.9% NaCl solution in the same volume. In animals, peripheral blood was determined by conventional methods: the number of red blood cells, hemoglobin, reticulocytes, platelets, white blood cells, white blood cell count, erythrocyte sedimentation rate (ESR), and erythrocyte resistance. Along with this, the content of total protein in blood serum was determined by the method of Lowry, potassium and sodium by plasma spectrophotometry. After the experiment was completed, a pathomorphological study of the brain and spinal cord, spinal ganglia, thyroid gland, parathyroid glands, adrenal glands, testes, pituitary gland, heart, lungs, aorta, liver, kidney, bladder, pancreas, stomach, small intestine, colon, thymus, spleen, lymph nodes, bone marrow.

When studying acute toxicity, it was found that a single administration of the studied peptide to animals at a dose exceeding the therapeutic recommended for clinical use by more than 5000 times does not cause toxic reactions, which indicates a large therapeutic breadth of the drug.

The study of subacute and chronic peptide toxicity indicates the absence of side effects with prolonged use of the drug in doses exceeding the therapeutic by 100-1000 times. When studying the effect of the peptide on the morphological composition of the blood of guinea pigs, an increase in the number of leukocytes was established 3 months after the start of drug administration, which normalized by the 6th month of observation (Table 2). The remaining indicators of the morphological composition of the blood of animals remained practically unchanged. There was no significant effect of the drug on ESR, erythrocyte resistance, and serum biochemical parameters.

When assessing the general condition of animals, morphological and biochemical parameters of peripheral blood, the morphological state of internal organs, the state of the cardiovascular and respiratory systems, and liver and kidney function, pathological changes in the body were not detected.

The absence of a general toxic effect makes it possible to recommend a pharmaceutical composition containing H-Glu-Asp-Gly-OH peptide as an active substance for clinical trials as a medicine used in clinical oncology for the treatment of tumors.

Table 1 Pharmaceutical composition based on a peptide having an antitumor effect Day after transplantation 3 eleven fourteen eighteen 21 25 28 31 Control - saline The average volume of tumors, mm ³ 0 162 358 919 1445 2456 4111 5916 average error 0 33 78 173 336 551 868 1094 Pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH at a dose of 0.1 μg / mouse × 20 The average volume of tumors, mm ³ 0 135 275 498 912 1559 2611 3663 average error 0 22 fifty 65 152 270 485 818 p 0.51 0.38 0,03 0.16 0.16 0.15 0.11 experience / control 0.84 0.77 0.54 0.63 0.63 0.64 0.62 tumor growth inhibition 16% 23% 46% 37% 37% 36% 38% Pharmaceutical composition containing the peptide H-Glu-Asp-Gly-OH at a dose of 2 μg / mouse × 20 The average volume of tumors, mm ³ 0 1161 202 564 940 1297 1995 1731 average error 0 39 63 113 167 447 431 436 p 0.38 0.12 0.09 0.14 0.08 0.04 0.002 experience / control 0.72 0.56 0.61 0.65 0.53 0.49 0.29 tumor growth inhibition 28% 44% 39% 35% 47% 51% * 71% * Cisplatin 5 mg / kg once The average volume of tumors, mm ³ 0 190 116 383 505 1127 1966 2371 average error 0 twenty 27 58 123 270 440 513 p 0.17 0.01 0.01 0.01 0.04 0.04 0.01 experience / control 0.67 0.32 0.42 0.35 0.46 0.48 0.40 tumor growth inhibition 33% 68% * 58% * 65% * 54% * 52% * 60% * * p <0.05 is statistically significant compared with the control.

table 2 Pharmaceutical composition based on a peptide having an antitumor effect Indicator The introduction of the peptide H-Glu-Asp-Gly-OH (1 μg / kg) 3 months 6 months Control (n = 24) Peptide (n = 24) Control (n = 24) Peptide (n = 24) Red blood cells, × 10 ¹² / l 5.3 ± 0.6 5.2 ± 0.1 5.4 ± 0.3 5.2 ± 0.7 Hemoglobin, g / l 14.2 ± 1.4 14.4 ± 0.9 14.5 ± 1.3 14.8 ± 1.1 Reticulocytes,% 1.3 ± 0.07 1.1 ± 0.08 1.1 ± 0.05 1.2 ± 0.04 Platelets × 10 ⁹ / L 143.7 ± 7.9 143.1 ± 4.5 144.5 ± 8.6 142.8 ± 6.2 White blood cells × 10 ⁹ / L 9.4 ± 0.5 11.8 ± 0.2 * 9.6 ± 0.5 10.3 ± 0.6 Band neutrons,% 0.31 ± 0.04 0.30 ± 0.02 0.33 ± 0.04 0.35 ± 0.01 Segmented neutrophils,% 45.8 ± 2.1 43.9 ± 1.8 46.2 ± 3.5 45.4 ± 3.0 Eosinophils,% 0.69 ± 0.05 0.67 ± 0.06 0.72 ± 0.04 0.73 ± 0.04 Basophils,% 0.61 ± 0.04 0.63 ± 0.03 0.72 ± 0.03 0.65 ± 0.08 Monocytes,% 2.5 ± 0.02 2.6 ± 0.01 2.6 ± 0.06 2.4 ± 0.04 Lymphocytes,% 48.9 ± 2.5 51.3 ± 2.2 51.3 ± 2.7 49.7 ± 1.9 ESR, mm / h 1.69 ± 0.05 1.98 ± 0.09 2.01 ± 0.05 1.85 ± 0.06 Erythrocyte resistance,% NaCl - maximum 0.41 ± 0.02 0.42 ± 0.02 0.42 ± 0.04 0.43 ± 0.02 - minimum 0.32 ± 0.05 0.31 ± 0.01 0.34 ± 0.04 0.33 ± 0.06 Total protein in blood serum, g / l 72.9 ± 3.1 73.6 ± 2.8 73.1 ± 3.4 72.3 ± 2.9 Sodium in blood serum, mmol / l 153.9 ± 5.7 155.6 ± 4.7 155.5 ± 6.2 155.2 ± 4.9 Serum potassium, mmol / l 5.1 ± 2.3 5.3 ± 2.0 5.2 ± 2.1 5.1 ± 2.5 * - p <0.05 compared with the control.

Claims (3)

1. A pharmaceutical composition having an antitumor effect, comprising as an active substance an effective amount of a peptide of the formula H-Glu-Asp-Gly-OH and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to claim 1, characterized in that it is in a form suitable for parenteral administration. 3. An agent having an antitumor effect, containing as an active substance an effective amount of a glutamyl-aspartyl-glycine peptide of the formula H-Glu-Asp-Gly-OH and a pharmaceutically acceptable carrier.