RU2761429C2 - Remedy with anti-tumor effect for treatment of oncological diseases - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: invention relates to the field of medicine, namely to oncology; it is intended for the treatment of tumor diseases of various location. A remedy with antiproliferative and antimetastatic properties is a complex of 3-(2–phenylethyl)-2-thioxo-1,3 thiazolidine-4-one with β-cyclodextrins. Components are used in the claimed amounts.

EFFECT: use of the invention provides for a stable remedy, which, in turn, allows for an increase in the treatment efficiency.

1 cl, 12 tbl, 1 ex

Description

The invention relates to a new agent, which is a clathrate complex of 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin. The specified complex can find application in medicine and pharmacology for the treatment of tumor diseases of various localization.

Currently, chemotherapy for oncological diseases is one of the main methods of their treatment. Modern drugs used for the treatment of oncological diseases are not effective enough and have a number of serious undesirable phenomena caused by a damaging effect on healthy organs and tissues. In this regard, the problem of finding low-toxic drugs with high therapeutic activity remains urgent. At the same time, successes in the development of new anticancer drugs are associated not only with the synthesis of new chemical compounds, but also, to a large extent, with the improvement of properties.

It is known that compound 3- (2-phenylethyl) -2-thioxo-4-thiazolidinone exhibits an antiproliferative effect on neuroblastoma cell culture N2A / US 2003/0195238, C07D207 / 44, publ. 10.16.2003 /.

It is also known that 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one has antiproliferative and antimetastatic action against tumor cells of Lewis epidermoid carcinoma implanted in mice / Patent for invention RF2522449, C07D277 / 36, publ ... 07/10/2014 /.

The available data on 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one and β-cyclodextrin as a carrier make it possible to create an effective and safe pharmaceutical clathrate complex and expand the arsenal of drugs for the treatment of oncological diseases. One of the components of the pharmaceutical composition 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one, being a multikinase inhibitor [Ana Martinez SAR and 3D-QSAR Studies on Thiadiazolidinone Derivatives: Exploration of Structural Requirements for Glycogen Synthase Kinase 3 Inhibitors / Ana Martinez et al. // J. Med. Chem. 2005, 48, 7103-7112], is aimed at both suppressing the proliferation of tumor cells and their metastasis, and inhibiting the growth of tumor vessels. Proliferation of tumor cells and vascularization (vascular growth) of a tumor are two important processes that ensure the growth of a malignant tumor. At the same time, the development of new clathrate complexes of active pharmaceutical ingredients with β-cyclodextrin will increase the solubility in water, improve bioavailability and, therefore, reduce their doses. The absence of low-dose highly effective drugs is an urgent technical problem of modern medicinal chemistry. Mechanochemistry is one of the promising directions in the development of such dosage forms. The creation of new dosage forms by the method of mechanochemical activation is based on the creation of a complex by combining β-cyclodextrin carriers with the pharmaceutically active substance 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one.

The technical result achieved by the present invention is to increase the efficiency, reduce the doses used.

The technical problem posed is solved by using a clathrate complex consisting of 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin, with the following content:

3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one 10 wt.% And β-cyclodextrin the rest, as an agent with antiproliferative and antimetastatic properties.

There is no information in the literature on the use of a clathrate complex consisting of 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin, with an active pharmaceutical ingredient content of 10 wt% and β-cyclodextrin the rest as an antiproliferative and antimetastatic agent for the treatment of cancer.

New in the proposed invention is that as a means of suppressing the proliferation and metastasis of various tumor cells can be used a clathrate complex consisting of 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin with a total the content of the active pharmaceutical substance is 10 wt% and β-cyclodextrin is the rest. For a person skilled in the art, these properties do not explicitly follow from the prior art.

The resulting clathrate complex is stable during storage and has been tested for antiproliferative and antimetastatic efficacy.

Statistical processing of research results was carried out using parametric and nonparametric methods. Differences between groups will be considered significant at p <0.05.

Complex - 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one in a complex with β-cyclodextrin.

Pharmaceutical substance (FS) - 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one

The essence of the invention is illustrated by examples of specific implementation.

Examples. The antitumor efficacy of PS 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one and its clathrate complex with β-cyclodextrin was evaluated in experiments on mice with implanted B16 melanoma and Lewis epidermoid carcinoma tumors and included the following studies:

▶ antiproliferative and antimetastatic effects of PS and the clathrate complex and the reference drug dacarbazine were carried out in an experiment on mice with implanted B16 melanoma tumor cells;

▶ antiproliferative and antimetastatic effects of PS and clathrate complex were carried out in an experiment on mice with implanted tumor cells of Lewis epidermoid lung carcinoma;

▶ Evaluation of the antimetastatic activity of PS and the clathrate complex in mice with implanted tumor cells of Lewis epidermoid lung carcinoma with removal of the primary tumor node.

Criteria for Evaluating the Effectiveness of Test Compounds

Antiproliferative efficacy was assessed by the change in the volume of the neoplasm. The volume of the neoplasm (V mm3) was calculated using the following formula (1):

V = a × b × c (1),

where a, b and c are the length, width and height of the tumor node.

Measurement times: 10-11, 15-16 and 20-21 days after implantation. Changes in the body weight of animals, the degree of inhibition of tumor growth, the inhibitory effect of tumor growth in terms of the logarithm of dead cells, and the effect of increasing the average life span were used as additional criteria.

The degree of tumor growth inhibition was determined by the tumor growth inhibition index (TPO), calculated according to the following formula (2):

TPO% = (Vcontrol - Vexperiment) / Vcontrol × 100, (2),

where V is the average tumor volume (mm3) in the treated and control group, respectively, for a specific period.

To assess the inhibitory effect of tumor growth by the logarithm of dead cells, their number in subcutaneously grafted B16 melanoma and Lewis epidermoid lung carcinoma was calculated. For this, in the control (t control) and treated (t experiment) groups, the mean time of doubling the tumor volume or reaching a certain value was determined. The difference between the indices "t control" and "t experience" (the time of delay in tumor growth in the treated groups in the groups) was in direct relation to the size of the pool of dead cells by this time. The lg of the number of dead cells (lg n) was calculated using the following formula (3):

Lg n = tk - to / 3.32Td, (3),

where tk - to is the delayed tumor growth in the experiment;

Td is the time of doubling the size of the tumor, calculated from the exponential curve of tumor growth in the control;

3.32 is the number of doubles required to increase lg n by one order of magnitude.

At the end of the experiments and the death of all animals, the effect of increasing their average life span was assessed. For this, the average life expectancy (life expectancy, days) in groups was determined and the indicator of increased life expectancy (life expectancy%) was calculated using the following formula (4):

UPL% = (SPZHopeta - SPZhkontrol) / SPZhkontrol × 100 (4)

Antimetastatic efficacy was assessed by the number of metastases in the lungs, which was determined 9-10 and 21 days after the start of the study drugs administration. For this purpose, lungs were removed from animals decapitated under anesthesia and transferred to Bouin's solution. Metastases were counted macroscopically. The intensity of the development of the metastatic process was assessed by the frequency of tumor metastasis (the percentage of animals with metastases in relation to their total number in the group), the degree of metastatic lung lesions according to the criteria developed by Tarin and Price, and the metastatic inhibition index (IMI), which was calculated using the formula (5):

(5),

(5),

where

Аk and А - frequency of metastasis to the lungs in mice of the control group and experimental;

Bk and B - the average number of metastases in the lungs in the control and experimental groups.

The study of the antiproliferative and antimetastatic properties of PS 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one and its clathrate complex with β-cyclodextrin, as well as the comparison drug dacarbazine, was carried out in an experiment on mice with implanted tumor cells melanoma B16.

The experiments were carried out on 210 male and female F1 CBA × C57Bl / 6 mice (body weight 18-22 g, age 2-2.5 months). The mice were divided into 7 groups of 30 animals of both sexes. Experimental groups, doses of test compounds and number of animals are shown in Table 1.

Table 1 - Experimental groups, doses of test compounds and number of animals

# # Groups Number of animals eleven Control (1% starch gel) - 30 ♂♀ 22 FS 20 mg / kg 30 ♂♀ 33 FS 40 mg / kg 30 ♂♀ 44 Complex 10 mg / kg 30 ♂♀ 55 Complex 20 mg / kg 30 ♂♀ 66 Complex 40 mg / kg 30 ♂♀ 77 Dakarbazine 5 mg / kg 30 ♂♀

A suspension of B-16 melanoma cells, in an amount of ~ 106 cells (~ 0.2 cm3), was implanted into the hind paw under the skin of the animals. Murine melanoma B-16 cells adapted for growing in a monolayer (cell bank of the Blokhin Russian Cancer Research Center) were cultured in RPMI-1640 medium supplemented with antibiotics (penicillin-streptomycin, 100 U / ml), 10% fetal calf ( 10% by volume) whey at a temperature of +37 ºC in an atmosphere containing 5% CO2. Sterile 75 cm3 mattresses (Corning, Nunc) were used as culture dishes. Re-sowing of the culture was carried out 3 times a week.

Dacarbazine was used as a reference drug. The comparison drug was administered every two days (a total of 8 doses) at a dose of 5.0 mg / kg. PS and Complex in a volume of 0.4 ml in 1% starch gel were introduced into the stomach with a metal probe for 21 days. Dacarbazine was injected intraperitoneally with a syringe as a solution. Control mice with implanted tumor were intragastrically injected with 1% starch gel in an amount of 0.4 ml per animal.

The results of the studies performed indicate that the administration of FS, the Complex and the reference drug dacarbazine to mice with implanted B16 melanoma tumor cells, dacarbazine, statistically significantly reduced their tumor volume in comparison with the control group (Table 2) already 10 days after tumor implantation. At the same time, the rate of inhibition of tumor growth in the treated groups was 32-47%. On the next day after tumor implantation, statistically significant differences from the control were obtained with the introduction of FS, Complex and dacarbazine in all studied doses. In this case, the best results were achieved in reducing the tumor volume and the effectiveness of tumor inhibition during the observed period of its development with the introduction of the Complex at doses of 10 and 20 mg / kg of body weight in mice. Compared with the reference drug and PS, administration of the Complex to mice at doses of 10 and 20 mg / kg provided a statistically significant inhibition of tumor growth.

Table 2 - Change in tumor volume (mm ³ ) and TPO,% in mice, depending on the dose of the study drugs

Groups and doses of administration Day after tumor implantation 10 15 twenty Average tumor volume SRW Average tumor volume SRW Average tumor volume SRW eleven Control (1% starch gel) 2151 ± 168 - 4189 ± 136 - 7702 ± 164 - 22 FS 20 mg / kg 1454 ± 89 ^* 32 2606 ± 148 ^* 38 4433 ± 129 ^* 42 33 FS 40 mg / kg 1264 ± 124 ^* 41 2285 ± 178 ^* 45 3683 ± 129 ^* 52 44 Complex 10 mg / kg 1108 ± 101 ^* 48 1908 ± 134 ^{* &} 54 3089 ± 168 ^{* # &} 60 55 Complex 20 mg / kg 1218 ± 97 ^* 43 1936 ± 179 ^{* &} 54 3171 ± 163 ^{* # &} 59 66 Complex 40 mg / kg 1258 ± 60 ^* 42 2157 ± 154 ^* 49 3376 ± 181 ^* 56 77 Dakarbazine 5 mg / kg 1382 ± 147 ^* 36 2551 ± 152 ^* 39 4371 ± 176 ^** 43

* P <0.00001-0.05 values in the experimental groups compared with the control;

** P <0.00001-0.05 values in group 7 compared with control;

# P <0.00001-0.05 values in groups 4 and 5 compared to group 7;

& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

The average lifespan of animals injected with the Complex at all studied doses increased compared to mice in the control group, dacarbazine and PS. The most significant data on the increase in the average lifespan of mice were obtained with the introduction of the Complex at doses of 10-40 mg / kg compared to animals that were injected with dacarbazine and PS (Table 3).

Table 3 - Tumor growth inhibitory effect on the logarithm of dead cells and the average lifespan of mice depending on the dose of the study drugs

Groups and doses of administration Day after tumor implantation Average lifespan of animals (days) Increase in the average life span of animals (%) 15 twenty lg number of dead cells
(lg n) lg number of dead cells
(lg n) eleven Control
(1% starch gel) - - 22.2 ± 1.3 - 22 FS 20 mg / kg 1.20 1.27 30.6 ± 0.8 ^* 38 33 FS 40 mg / kg 1.30 1.53 35.2 ± 0.9 ^* 59 44 Complex 10 mg / kg 1.54 1.73 38.8 ± 0.6 ^{* # &} 75 55 Complex 20 mg / kg 1.67 1.67 37.6 ± 0.9 ^{* # &} 69 66 Complex 40 mg / kg 1.45 1.66 36.7 ± 0.8 ^* 65 77 Dakarbazine 5 mg / kg 1.19 1.27 31.0 ± 1.0 ^** 40

^* P <0.00001-0.05 values in the experimental groups compared with the control;

^** P <0.00001-0.05 values in group 7 compared with control;

^# P <0.00001-0.05 values in groups 4 and 5 compared to group 7.

^& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

Administration of dacarbazine, PS and Complex to tumor-bearing mice at all studied doses leads to an increase in the lg n number of dead cells and these values are higher than 0.7, which may indicate their high activity. It should be noted that the greatest inhibitory effect on tumor growth in terms of the logarithm of dead cells was achieved when the Complex was administered to mice at doses of 10-40 mg / kg (Table 3).

When analyzing the number of metastases in the lungs, a statistically significant decrease was found in comparison with the control, dacarbazine and PS for tumor-bearing mice of the study groups, which were injected with the Complex in all administered doses (Table 4). It should also be noted that the best results were achieved, as in the case of a decrease in tumor volume with the introduction of the Complex at doses of 10 and 20 mg / kg.

Table 4 - The number of metastases in the lungs depending on the dose of the study drugs

Groups and doses of administration Number of metastases, pcs. eleven Control (1% starch gel) 38.1 ± 2.1 22 FS 20 mg / kg 25.3 ± 1.6 ^* (p <0.05) 33 FS 40 mg / kg 20.0 ± 2.8 ^* (p <0.01) 44 Complex 10 mg / kg 14.8 ± 2.2 ^{* # &} (p <0.003) 55 Complex 20 mg / kg 14.1 ± 2.0 ^{* # &} (p <0.001) 66 Complex 40 mg / kg 14.0 ± 3.0 ^{* &&} (p <0.001) 77 Dakarbazine 5 mg / kg 25.0 ± 1.7 ^** (p <0.05)

^* P <0.00001-0.05 values in the experimental groups compared with the control;

^** P <0.00001-0.05 values in group 7 compared with control;

^# P <0.00001-0.05 values in groups 4 and 5 compared to group 7;

^& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

The study of the antitumor activity of PS, the Complex and the reference drug cisplatin was carried out in an experiment on mice with implanted tumor cells of Lewis epidermoid carcinoma of the lung.

The experiments were carried out on 210 male and female F ₁ CBA × C57Bl / 6 mice (body weight 19-21 g, age 2-2.5 months). A suspension of Lewis epidermoid carcinoma cells, in an amount of ~ 106 cells (~ 0.2 cm ³ ), was implanted into the hind paw under the skin of mice. The cells of the Lewis murine epidermoid carcinoma were obtained from the cell bank of the V. N.N. Blokhin.

The mice were divided into 7 groups of 30 animals of both sexes. Experimental groups, doses of tested compounds and number of animals are shown in Table 5. Cisplatin was used as a reference drug. PS and Complex in a volume of 0.4 ml in 1% starch gel were introduced into the stomach with a metal probe for 21 days. The reference drug cisplatin at a dose of 3.5 mg / kg (per injection) was injected 3 times within 21 days with a syringe in the form of a solution for injection in a volume of 0.2 ml intraperitoneally. Control mice with implanted tumor were intragastrically injected with 1% starch gel in an amount of 0.4 ml per animal.

Table 5 - Experimental groups, doses of test compounds and number of animals

# # Groups Quantity
animals eleven Control (1% starch gel) - 30 ♂♀ 22 FS 20 mg / kg 30 ♂♀ 33 FS 40 mg / kg 30 ♂♀ 44 Complex 10 mg / kg 30 ♂♀ 55 Complex 20 mg / kg 30 ♂♀ 66 Complex 40 mg / kg 30 ♂♀ 77 Cisplatin 3.5 mg / kg 30 ♂♀

The results of the studies show that the administration of cisplatin, PS and the Complex to mice with implanted tumor cells of Lewis epidermoid carcinoma statistically significantly reduces their tumor volume compared to animals in the control group (Table 6) already 11 days after tumor inoculation. At the same time, the rate of inhibition of tumor growth in the treated groups was 26-47%. On the next day after tumor implantation, statistically significant differences persisted with the introduction of cisplatin, PS and Complex in all studied doses. In this case, the best results were achieved in reducing the tumor volume and the effectiveness of inhibition of tumor growth during the observed period of its development with the introduction of the Complex at doses of 10 and 20 mg / kg of body weight in mice. Compared with cisplatin and PS, administration of the Complex to mice at doses of 10 and 20 mg / kg provided statistically significant inhibition of tumor growth.

Table 6 - Change in tumor volume (mm ³ ) and TPO,% in mice depending on the dose of the study drugs

Groups and doses of administration Day after tumor implantation eleven sixteen 21 Average tumor volume SRW Average tumor volume SRW Average tumor volume SRW eleven Control (1% starch gel) 2314 ± 112 - 4410 ± 147 - 8316 ± 174 - 22 FS 20 mg / kg 1706 ± 101 ^* 26 2943 ± 114 ^* 33 5311 ± 128 ^* 36 33 FS 40 mg / kg 1411 ± 124 ^* 39 2632 ± 222 ^* 40 4487 ± 117 ^* 46 44 Complex 10 mg / kg 1247 ± 165 ^* 46 2016 ± 165 ^{* # &} 54 3660 ± 157 ^{* # &} 56 55 Complex 20 mg / kg 1217 ± 173 ^* 47 2220 ± 189 ^{* &} 50 3808 ± 147 ^{* # &} 54 66 Complex 40 mg / kg 1397 ± 114 ^* 40 2361 ± 232 ^* 46 4063 ± 209 ^* 51 77 Cisplatin 3.5mg / kg 1590 ± 136 ^* 31 2888 ± 218 ^* 35 5061 ± 201 ^** 39

^* P <0.00001-0.05 values in the experimental groups compared with the control;

^** P <0.00001-0.05 values in group 7 compared with control;

^# P <0.00001-0.05 values in groups 4 and 5 compared to group 7;

^& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

The average lifespan of animals that were injected with cisplatin, PS and Complex in all studied doses increased by 37-60% compared to mice in the control group. The most statistically significant data on the increase in the average lifespan of mice compared to animals injected with cisplatin and PS were obtained with the introduction of the Complex at doses of 10-40 mg / kg (Table 7).

Table 7 - Tumor growth inhibitory effect on the logarithm of dead cells and the average lifespan of mice depending on the dose of administration of the studied drugs

Groups and doses of administration Day after tumor implantation Average lifespan of animals (days) Increase in the average life span of animals (%) sixteen 21 lg number of dead cells (lg n) lg number of dead cells (lg n) eleven Control (1% starch gel) 25.7 ± 1.2 22 FS 20 mg / kg 1.17 1.15 35.3 ± 1.0 ^* 37 33 FS 40 mg / kg 1.18 1.35 36.8 ± 1.1 ^* 43 44 Complex 10 mg / kg 1.62 1.47 41.2 ± 1.8 ^{* # &} 60 55 Complex 20 mg / kg 1.34 1.50 40.4 ± 1.3 ^{* # &} 57 66 Complex 40 mg / kg 1.38 1.43 39.9 ± 1.1 ^{* &} 53 77 Cisplatin 3.5mg / kg 1.14 1.22 36.6 ± 1.1 ^** 42

^* P <0.00001-0.05 values in the experimental groups compared with the control;

^** P <0.00001-0.05 values in group 7 compared with control;

^# P <0.00001-0.05 values in groups 4 and 5 compared to group 7;

^& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

When analyzing the number of metastases in the lungs, a statistically significant decrease was found in comparison with the control for tumor-bearing mice of the study groups, which were injected with cisplatin, PS and Complex in all administered doses (Table 8). It should be noted that the best results were achieved, as in the case of a decrease in tumor volume, with the introduction of the Complex at doses of 10 and 20 mg / kg in comparison with PS and cisplatin.

Table 8 - The number of metastases in the lungs depending on the dose of the study drugs

Groups and doses of administration Number of metastases, pcs. eleven Control (1% starch gel) 52.2 ± 2.8 22 FS 20 mg / kg 37.1 ± 1.9 ^* 33 FS 40 mg / kg 30.6 ± 1.3 ^* 44 Complex 10 mg / kg 23.9 ± 1.7 ^{* # &} 55 Complex 20 mg / kg 24.1 ± 1.5 ^{* # &} 66 Complex 40 mg / kg 27.8 ± 2.7 ^* 77 Cisplatin 3.5 mg / kg 35.7 ± 2.1 ^**

^* P <0.00001-0.05 values in the experimental groups compared with the control;

^** P <0.00001-0.05 values in group 7 compared with control;

^# P <0.00001-0.05 values in groups 4 and 5 compared to group 7;

^& P <0.00001-0.05 values in groups 4 and 5 compared to group 2.

Evaluation of the antimetastatic activity of PS and the Complex was carried out on mice with implanted Lewis epidermoid lung carcinoma with removal of the primary tumor node.

The experiments were carried out on 180 male and female F1 CBA × C57Bl / 6 mice (body weight 18-21 g, age 2-2.5 months).

A suspension of Lewis epidermoid carcinoma cells, in an amount of ~ 106 cells (~ 0.2 cm3), was implanted into the hind foot pad of mice. The cells of the Lewis murine epidermoid carcinoma were obtained from the cell bank of the V. N.N. Blokhin. On the 15th day after inoculation of Lewis epidermoid carcinoma cells, amputation of the paws with a tumor along the knee joint was carried out under ether anesthesia with the application of a pulling tourniquet in mice. The surgical wound was treated with medical glue.

The mice were divided into 6 groups of 30 animals of both sexes. Experimental groups, doses of tested compounds and number of animals are shown in Table 9. PS and Complex were injected into the stomach with a metal probe in 1% starch gel in a volume of 0.4 ml per mouse. The introduction of the FS and the Complex began 1 hour before the operation and continued to be administered daily for 9 days. Half of the animals from each group were retained to evaluate the effectiveness of therapy for increasing their average life expectancy. Mice of the control groups with and without tumor removal were intragastrically injected with 1% starch gel in an amount of 0.4 ml per animal.

Table 9 - Experimental groups, doses of test compounds and number of animals

# # Groups Quantity
animals eleven Control without tumor removal (1% starch gel) - 30 ♂♀ 22 Control with tumor removal (1% starch gel) - 30 ♂♀ 33 FS (with tumor removal) 20 mg / kg 30 ♂♀ 44 FS (with tumor removal) 40 mg / kg 30 ♂♀ 55 Complex (with tumor removal) 10 mg / kg 30 ♂♀ 66 Complex (with tumor removal) 20 mg / kg 30 ♂♀

The results of the conducted studies indicate that the administration of the Complex to mice with implanted epidermoid carcinoma of the lung Lewis with the removal of the primary tumor node provided an increase of 56-57% in comparison with mice of the control group (with the removed primary tumor node) and FS in the average life expectancy of animals (Table 10) ...

Table 10 - Average lifespan of mice depending on the dose of the study drugs

Groups and doses of administration Average lifespan of animals (days) Increase in the average life span of animals, (%) The number of surviving animals,% eleven Control without tumor removal (1% starch gel) 26.9 ± 1.6 - 6,7 22 Control with tumor removal (1% starch gel) 37.2 ± 1.3 # 38 13.3 33 FS (with tumor removal) 20 mg / kg 43.8 ± 1.1 # eighteen 38.2 44 FS (with tumor removal) 40 mg / kg 50.7 ± 1.2 # 35 54.4 55 Complex (with tumor removal) 10 mg / kg 58.3 ± 1.8 * ¤ & 57 63.3 66 Complex (with tumor removal) 20 mg / kg 58.1 ± 2.3 * ¤ & 56 60.0

^* P <0.00001-0.05 values in groups 5 and 6 compared with group 2;

^# P <0.00001-0.05 values in group 2 compared with group 1;

^¤ P <0.00001-0.05 values in groups 5 and 6 compared to group 1.

^& P <0.00001-0.05 values in groups 5 and 6 compared to groups 3 and 4.

When analyzing the number of metastases in the lungs, a statistically significant decrease was found in comparison with animals of the control groups (with and without removal of the tumor) and PS for mice of the study groups with the removed primary tumor node, which were injected with the Complex at doses of 10 and 20 mg / kg. It should also be noted that a favorable picture in terms of the degree of the least metastatic lesion of the lungs of mice was found in groups with a removed primary tumor node when the Complex was administered at doses of 10 and 20 mg / kg (Table 11).

Table 11 - The number of metastases in the lungs and their degree of damage depending on the dose of the study drugs

Groups and doses of administration Average number of metastases, pcs. The degree of metastatic lesions of the lungs depending on the number and size of metastases 0 one 2 3 4 eleven Control without tumor removal (1% starch gel) 51.0 ± 2.2 - 4.1 21.5 11.5 3.0 22 Control with tumor removal (1% starch gel) 41.0 ± 1.4 ^# 3.0 7.1 22.6 8.0 - 33 FS (with tumor removal) 20 mg / kg 30.0 ± 1.2 ^# 7 6 eight 5 - 44 FS (with tumor removal) 40 mg / kg 26.0 ± 1.0 ^# 9 eight 7 3 - 55 Complex (with tumor removal) 10 mg / kg 18.0 ± 1.7 ^{* ¤ &} thirteen 12.4 6.1 - - 66 Complex (with tumor removal) 20 mg / kg 20.3 ± 1.4 ^{* ¤ &} 12 10.7 7.2 2.4 -

^* P <0.00001-0.05 values in groups 5 and 6 compared with group 2;

^# P <0.00001-0.05 values in group 2 compared with group 1;

^¤ P <0.00001-0.05 values in groups 5 and 6 compared to group 1.

^& P <0.00001-0.05 values in groups 5 and 6 compared to groups 3 and 4.

The introduction of the Complex at doses of 10 and 20 mg / kg to mice with removed primary tumor nodes in comparison with the control groups and FS provided effective inhibition of the metastatic process, as evidenced by the data presented in Table 12.

Table 12 - Effect of PS and Complex on the intensity of the metastatic process in mice

Groups and doses of administration Metastasis rate (%) IM eleven Control without tumor removal (1% starch gel) one hundred - 22 Control with tumor removal (1% starch gel) 87 18.5 33 FS (with tumor removal) 20 mg / kg 75 40.6 44 FS (with tumor removal) 40 mg / kg 65 48.8 55 Complex (with tumor removal) 10 mg / kg 57 55.4 66 Complex (with tumor removal) 20 mg / kg 60 52.3

As a result of the studies carried out on the antitumor effect of the clathrate complex - 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin, it was found that the studied Complex has a pronounced antiproliferative and antimestatic effect against tumors such as melanoma B16 and Lewis epidermoid carcinoma. The use of the Complex in tumor-bearing mice in comparison with FS provides effective inhibition of tumor growth, an increase in the average duration of animals, and a decrease in the number of metastases in the lungs.

It should be noted that the Complex has a fairly high anti-metastatic effect. The use of the Complex in mice with a removed primary tumor node provided effective inhibition of the metastatic process, an increase in the average duration of animals, and a decrease in the number of metastases in the lungs.

The best results were achieved with the introduction of the Complex in comparison with FS at doses of 10-20 mg / kg. In the experiments carried out, the Complex was superior to the reference drugs dacarbazine and cisplatin in terms of its antitumor effect.

The proposed invention provides an increase in efficiency, a decrease in the doses used and an expansion of the arsenal of agents for the treatment of various types of tumor diseases.

Claims (3)

A drug with antiproliferative and antimetastatic properties, consisting of 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one with β-cyclodextrin with the following content: 3- (2-phenylethyl) -2-thioxo-1,3 thiazolidin-4-one - 10 wt.%, β-cyclodextrin - the rest.