Antitumor agent

 

(57) Abstract:

Proposed: the use of Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid, previously known as a stabilizer of cell membranes, as antineoplastic agents, as well as means, inhibiting metastasis. The invention expands the Arsenal of tools stated purpose, and also to augment therapeutic effect of other anti-cancer drugs. 5 table.

The invention relates to new biologically active substances from the class alkenylboronic acids and can be used in medicine and biology as the basis for making medicines.

Despite the existence in clinical practice more than 60 anticancer drugs, the effectiveness of most of them is insufficient and range of cancer that is sensitive to chemotherapy, limited. Among the most available and currently used drugs known drugs such as cisplatin and 5-fluorouracil, which are used separately or in complex therapy of gastric cancer, colon cancer, breast cancer, liver cancer (hepatoma), melanoma and others (Anticancer chemioterapia physician in clinical pharmacology - a guide for physicians. - SPb. - 2001. S. 615).

Like most drugs used for the treatment of malignant diseases, cisplatin and 5-fluorouracil are highly toxic if used, as a rule, are nausea, vomiting, expressed violations of function of kidneys, disorders of the nervous system, bone marrow suppression, etc. (Mashkovsky M. D. Medicines. - M - 2001. C. 425-428).

The development of new, more active against malignant neoplasm of medicines, is effective in tumors with primary or acquired resistance to known anticancer drugs, is an important direction of research in the field of modern pharmacology and Oncology.

The aim of the invention is the creation of new antitumor agents.

As antineoplastic agents are encouraged to use the heterocyclic compound is Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid, which has the properties of the stabilizer of cell membranes (Clinical efficacy and safety of cephalosporin antibiotics production LLC abled. - Proceedings of NIIKI, Audioapparaat activity of Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid (hereinafter connection) in the system in vitro cell tumors of various types, as well as in vivo in strains of mice that transplanted cell tumors.

As a reference preparations for testing the anticancer activity of the compounds were used cisplatin and 5-fluorouracil.

Studies have shown that the test compound exhibits in the system in vitro and in vivo expressed antitumor properties.

In this work, we used tumor cell lines (P 815, B16, L1210, policy number G27) and healthy adult animals - mouse C57B1/6 and CBA both sexes, 8-, 10-weeks of age, weighing 18-20 g (variation in the groups of animals on the initial body weight did not exceed ±10%). Control and experimental animals were obtained simultaneously from the same kennel ("the Dawn", Tomsk). Before and during the experiment control and experimental animals were kept in a vivarium under the same conditions: in standard plastic cages with fine wood shavings (not more than 10 animals in one cage) on a standard diet. All studies were conducted at the same time of day (in the morning).

Example 1. Evaluation of the antitumor properties of the compounds in vitro

Evaluation of the antitumor properties of the connection provocatively at a concentration of 10×103well, incubated with the compound for 24 hours, 6 hours before the end of the incubation was made 1 ci N3-thymidine. After incubation, the cells were collected on glass-fiber filters (Flow Lab) using a machine Harvester (Titertek). The results were expressed in counts/min included thymidine on 10×103cells (average data for the triplet). The degree of suppression of the growth of tumor cells under the influence of the tested compounds was calculated by the formula: N=(experiment/control)·100%. In the tables presents data on the inhibition of the proliferative activity of tumor cells under the action of the compound relative to the control values proliferative activity of these cells.

The connection was tested in doses 5, 25, 50, 75, 100, 150 and 300 g/ml as a control anticancer drug used 5-fluorouracil (5-FU) at a dose of 5, 25 and 50 mg/ml

In table 1 and 2 presents data on the cytotoxic effect of the compounds in vitro on tumor cells of various origins.

We found that the in vitro system connection has a dose-dependent cytotoxic (inhibitory) effect on the growth of tumor cells of all 4 types, with the maximum effect (89-99% suppression of cell Rho is Ino greater inhibitory effect against cell lines B17 and policy number G27, in comparison with the known drug 5-fluorouracil.

Thus, according to the results of the studies in the in vitro system can be argued that Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid is a new highly effective in inhibiting the growth of tumor cells, which in comparable doses significantly higher than the effect of 5-fluorouracil.

Example 2. Evaluation of the antitumor properties of the compounds in vivo.

1. The effect of compounds on the metastasis of melanoma cells.

The B16 melanoma cells intravenously transplanted to C57BL/6 mice at a dose of 200×103Jr.

The connection in different doses were administered for 10 days once daily intraperitoneally daily (starting from 1 day after inoculation of B16 melanoma). Conducted accounting of lung metastases on day 15 after inoculation of tumor cells. Table 3 presents data on the impact of connections on the metastasis of B16 melanoma cells in the lungs.

As is seen in table 3, the compound exhibits pronounced antimetastatic properties in respect of B16 melanoma cells in a dose of 25 mg/kg

2. The effect of compounds on Metastasio the ohms policy number G27 in a dose of 100×103/ml. Accounting of lung metastases was performed on day 26 after inoculation of the tumor. For inhibition of growth of metastases used cisplatin at a dose of 5 mg/kg and the compound at a dose of 10, 25 and 100 mg/kg Cisplatin and compound was administered once daily intravenously daily for 6 consecutive days, starting from the day of tumor inoculation.

As can be seen from table 4, the compound at a dose of 25 and 100 mg/kg, administered daily intravenously for 6 days at 35% and 38%, respectively, inhibits metastasis of hepatoma cells policy number G27 in the lungs, whereas cisplatin in equivalent therapeutic dose (based on LD50 single dose of cisplatin (5 mg/kg corresponds to a single dose of the studied compounds 100-250 mg/kg ) inhibits the formation of metastases by 23.5% (i.e. 1.6 times less efficient).

3. The effect of combined application of connection with cisplatin in the process of metastasis of melanoma In 16 in the lungs

The B16 melanoma cells intravenously transplanted to C57BL/6 mice at a dose of 100×103/ml. With the introduction of combination cisplatin + connection used the following doses for each drug (2.5 mg/kg cisplatin + 50 mg/kg of compound). The combination of drugs was administered daily, once a day is ovali cisplatin at a dose of 5 mg/kg, and the connection at the dose of 100 mg/kg

The number of lung metastases was performed on day 15 after inoculation of tumor cells. Table 5 presents data on the impact of the combination of cisplatin + connection on the process of metastasis of B16 melanoma cells in the lungs.

As is seen in table. 5 data, the introduction of cisplatin at a dose of 5 mg/kg 49% inhibits melanoma metastasis In 16 into the lungs; the introduction of the compound in a dose of 100 mg/kg by 26%, respectively, and the combination of cisplatin with connection in half-doses - 69%, respectively. I.e., on the model of metastasis of melanoma In 16 in light detected potentiating effect of combined application widely used in clinical Oncology drug cisplatin and the new connection is the effect of the combination is less than the total effect of both plants, but higher than the introduction of each of them. Given that in the studied combinations, the toxic dose of cisplatin was two times less compared to therapeutic, the proposed connection can be considered as a promising anticancer compounds for combined use with known anticancer means to reduce their terapeutiche what I antitumoral action.

Conducted in in vitro systems and in vivo studies allow us to ascertain the presence of Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid a strong antitumor activity. This compound is promising as an independent antitumor agent of a new class, and as a means for the combined use with other anticancer drugs with the purpose of potentiating therapeutic effect.

The use of Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acids as antitumor agents.



 

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