JPH0136446B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antitumor agent containing lactose fatty acid ester as an active ingredient. Many antitumor agents have been known that use chemically synthesized substances as active ingredients, but they are highly toxic and have strong side effects, and their administration can also harm the normal tissues of the human body. For these reasons, there is currently no known synthetic antitumor agent that can be used with confidence. In recent years, semi-synthetic anti-tumor active substances such as
Sucrose fatty acid esters, trehalose fatty acid esters, maltose fatty acid esters, and glucose fatty acid esters have a remarkable survival effect on Ehrlich ascites cancer; however, sarcoma180
Research results have been reported such as no effect on solid cancer [Chem.Pharm.Bull, 23 , p. 597~
603 (1975), 24 , 387-393, 756-762
(1976), 25 , pp. 624-631, pp. 2378-2384
Page (1977), 27 , 2011-2015, 2016-
2020 p. (1979), 29 , p. 505-513, p. 878-
880 pages, 881-883 pages (1980), Proceedings of the Pharmaceutical Society of Japan, 1976, 265 pages, 1977, 51 pages, 1979, 544 pages,
1980, 398 pages]. The present inventors focused on these research reports, and found that they have emulsifying properties, excellent permeability,
In addition, focusing on the rapid decomposition of the product, we synthesized esters of various other sugars and fatty acids.
As a result of repeated research on their antitumor effects,
Esters of lactose and specific fatty acids are highly safe substances with no side effects, have a remarkable suppressive effect on transplanted solid tumors and ascites-type tumors, and exhibit strong antitumor effects when administered intravenously. I discovered that. The present invention is as follows. (1) An antitumor agent containing lactose stearate, which is a condensation of lactose and stearic acid, or lactose oleate, which is a condensation of lactose and oleic acid, as an active ingredient. (2) The antitumor agent according to claim 1, which contains as an active ingredient an ester in which 1 mole of lactose is condensed with 1 mole of stearic acid or oleic acid. In the case of esters that are the condensation of lactose and fatty acids other than stearic acid or oleic acid,
It has a strong hemolytic effect, has side effects, reduces antitumor activity, and also reduces aqueous solution and emulsifying properties. To produce the ester of the present invention, for example, lactose and fatty acid may be dehydrated and condensed in the presence of a dehydrating agent, or lactose and fatty acid methyl ester may be condensed in the presence of a catalyst, but the halogen of the fatty acid Condensation with lactose in the presence of a dehydrohalogenating agent is advantageous (see JAOCS, 51 , pp. 8-11 (1974); JAOCS , 52, pp. 256-258 (1975)). Lactose fatty acid ester, which is an active ingredient of the present invention, is soluble in cold water or hot water, and its aqueous solution is an emulsifying substance that has an extremely high ability to lower surface tension. Particularly preferred are esters into which 1 mole of fatty acid has been introduced. All of the esters that are the active ingredients of the present invention are white to light brown powders and are tasteless and odorless. These active ingredients are usually dissolved or suspended in physiological saline and administered orally, intravenously, or the like. In order to confirm the efficacy of the antitumor agent of the present invention, mice (warm-blooded (animal) was used as a model for the experiment. As a result, the antitumor agent of the present invention has a remarkable suppressive effect on transplanted solid tumors and ascites-type tumors when administered intraperitoneally, and does not cause severe side effects even when administered intravenously. was found to have strong antitumor effects. The antitumor agent of the present invention is characterized by its lack of toxicity, and in addition to its strong antitumor properties, it has emulsifying properties, so it can be used in combination with other water-insoluble anticancer agents, making it extremely useful. . The dosage of the antitumor agent of the present invention varies depending on the type of tumor, the degree of progression thereof, the route of administration, the number of days of administration, etc.
10-5 mg/Kg (body weight), 1-5 mg/kg for intravenous injection
Kg (weight) is appropriate. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 (A) Lactose stearate monoester (LMS)
Production of 30 g of lactose [4-O-(β-D-galactopyranosyl)-D-glucopyranose] with anhydrous N,
In 200ml of N-dimethylformamide (DMF)
After heating and dissolving at 120℃, the solution was cooled to 60℃,
20 ml of anhydrous pyridine was added. To this solution, add 50% by weight of stearoyl chloride/
30 ml of DMF solution was added and stirred for about 2 hours to react. After the reaction was completed, DMF was distilled off under reduced pressure to obtain syrup. Ethyl ether was added to this syrup to dissolve unreacted fatty acids, and the residue was dissolved in n-butanol with heating. Water was added and shaken, and the separated butanol layer was collected and concentrated under reduced pressure. Ethyl ether was further added to the concentrate to precipitate crude LMS. The obtained crude LMS was adsorbed on a silica gel chromatograph and eluted with various solvents to separate it into an ethyl ether eluted fraction, an acetone eluted fraction and a methanol eluted fraction, and the obtained methanol eluted fraction was concentrated to dryness under reduced pressure. Purified LMS was obtained. The obtained purified LMS has a sharp absorption at 1730 cm due to the ester bond between lactose and stearic acid in the infrared absorption spectrum obtained by the KBr tablet method.
^-1 existed. Also ^, _13C by _{C2D6SO4 solution}
From the NMR chart, there were 60.5 to 103.9 ppm of signal derived from the carbohydrate moiety and 14 to 30 ppm of signal derived from the fatty acid moiety. (B) Production of antitumor agent Dissolve purified LMS in physiological saline,
A 1% by weight aqueous solution was prepared. (C) Type of tumor and inoculation method The tumor cells used in the experiment were Ehrlich ascites cancer cells and sarcoma180 cells. It was replaced by In the experiment, cells from ascites were taken out one week after inoculation, and Ehrlich ascites cancer cells and sarcoma180 cells were collected.
0.1 ml of physiological saline containing about 4 million cells each was implanted intraperitoneally or subcutaneously in the lower right flank of test mice. (D) Administration method of antitumor agent The above LMS-containing physiological saline solution was sterilized by heating to 121°C for 10 minutes, and 10mg/Kg (mouse body weight) per day for solid tumors and ascitic fluid. For type tumors, the drug was administered intraperitoneally every day for 9 days at a dose of 200 mg/Kg (mouse body weight) per day. In addition, in the experiment, 10 mice were used, and 10 mice that were not administered were used as controls. (E) Experimental Results In the experiment, the inhibition rate for solid tumors and the survival rate for ascites-type tumors were calculated as follows. [Suppression rate] Thirty days after transplantation, the mouse was dissected, the grown solid tumor was excised, its weight was measured, and the suppression rate was calculated using the following formula. Suppression rate = (C _s − T _s ) / C _s × 100 However, C _s : Average tumor weight of control group T _s : Average tumor weight of test group [survival extension rate] Survival extension rate = T _A /C _A × 100 , T _A : Average survival days of the test group C _A : Average survival days of the control group As a result of the experiment, when S-180 was inoculated into ICR mice, the inhibition rate of solid tumors was 69.2%, and ascites-type tumors were suppressed by 69.2%. The survival rate was 180%, and the suppression rate was 180% compared to the ICR inoculated with Ehrlich ascites cancer cells.
The survival rate was 55.2%, and the survival rate was 129%. Example 2 According to Example 1, lactose oleate (LMO) was synthesized, and the purified product was dissolved or suspended in physiological saline to prepare an administration agent, and its antitumor effect was investigated. In the experiment, the LMS prepared in Example 1
The study was conducted by changing the drug, tumor type, drug dose, and administration method. The experimental conditions and results are summarized in the table below. Table 1 shows the antitumor effect of the antitumor agent of the present invention on solid tumors, and Table 2 shows the antitumor effect on ascites-type tumors.

【table】

[Table] As is clear from both of the above tables, the antitumor agent of the present invention has excellent effects. Example 3 Toxicity experiment of antitumor drugs LMS and LMO were administered to mice at 1g/1 each.
When administered orally by force every day at a dose of Kg/day, no abnormalities were observed, and autopsy examination two weeks later revealed that all organs were normal. There were no deaths at all after 10 consecutive days of intraperitoneal administration of 300 mg/Kg/day, and no deaths were observed even after 10 consecutive days of intravenous administration of 20 mg/Kg/day, which seemed to be an excessive dose. I couldn't help it. Furthermore, regarding the acute toxicity of the antitumor agent of the present invention, in the case of LMS, the LD ₅₀ for ICR female mice (25 g) was 839 mg/Kg or more when administered intraperitoneally. This shows that the antitumor agent of the present invention is extremely safe and has substantially no toxicity.

Claims (1)

[Scope of Claims] 1. An antitumor agent containing lactose stearate, which is a condensation of lactose and stearic acid, or lactose oleate, which is a condensation of lactose and oleic acid, as an active ingredient. 2. The antitumor agent according to claim 1, which contains as an active ingredient an ester in which 1 mole of lactose is condensed with 1 mole of stearic acid or oleic acid.