JPH07100659B2 - Cell differentiation inducer - Google Patents

Description

TECHNICAL FIELD The present invention relates to a cell differentiation inducer, and more specifically, it contains a cell differentiation inducer clinically useful as an anticancer agent and the like, and the cell differentiation inducer as an active ingredient. The present invention relates to a composition for inducing cell differentiation.

(Prior Art) Conventionally, as cancer chemotherapeutic agents, alkylating agents (nitrodiene mustards, ethyleneimines, sulfonates, etc.), antimetabolites (folic acid antagonists, pyrimidine antagonists, etc.), plant-based agents Clinically used fission toxins (colcemid, vinblastine, etc.), antibiotics (sarcomycin, carcinophylline, mitomycin, etc.), hormonal agents (corticosteroids, male and female hormones, etc.), and porphyrin complex salts (morphylin, copp), etc. Has been done. However, most of these cancer chemotherapeutic agents are cytotoxic substances, and there has been a problem that serious side effects are exhibited depending on the dose and administration method. Therefore, it has been desired to develop an antitumor agent having low toxicity and excellent antitumor activity.

On the other hand, it is expected that cancer cells will be applicable to cancer treatment if they can be differentiated by some kind of stimulus, because they recognize that normal cells repeat proliferation while being undifferentiated during differentiation. .

(Problems to be Solved by the Invention) Accordingly, an object of the present invention is to provide a cell differentiation inducer which is excellent in cell differentiation inducing activity and which is useful as a carcinostatic agent in the clinic by differentiating cancer cells into normal mature cells. To do.

Another object of the present invention is to provide a cell differentiation inducer composition containing the cell differentiation inducer as an active ingredient.

(Means for Solving the Problems) As a result of earnest search for a compound having an excellent cell differentiation inducing activity to solve the above problems, the present inventor found that cotylenin C having the following structure has an extremely excellent cell differentiation inducing activity. In addition, it was found that cotyrenin C is useful as an anticancer agent by causing normal differentiation of cancer cells, and completed the present invention.

Cotylenin C is a plant-active glycoside having the following structure, and is known to have plant growth promoting activity (T.
Sassa et al. Agr. Biol. Chem, 39 (11) 2213-2215,197
Five).

Cotylenin C was a new strain of Cladosporium (strain 501-7W), which was shaken for 4 days at 28 ° C in a medium containing 3% sucrose, 0.5% peptone and 0.5% corn steep. After culturing, 0.5% calcium carbonate was added, and the mixture was further cultivated with shaking at 28 ° C for 2 days. The obtained culture filtrate was extracted with ethyl acetate, and the extract was concentrated under reduced pressure and subjected to silica gel column chromatography (trichloromethane: It can be obtained by adding ethanol = 100: 4). Usually, 25 mg of cotylenin C is obtained from the culture solution 5.

The present invention provides a novel use of cotylenin C as a cell differentiation inducer.

The cell differentiation inducing activity of cotyrenin C will be described below with reference to Examples.

(Example) Mouse myeloid leukemia cel
l, M1) test GIBCO Eagle MEM medium supplemented with 10% horse serum and 60 mg / kanamycin was inoculated with M1 cells at 5.0 × 10 ⁴ cells / ml, and a predetermined amount of this was inoculated. Test compound was added (final volume 5 ml).

After culturing in 7.5% CO ₂ at 37 ° C. for 7 days, lysozyme activity induced by differentiation into phagocytes or granulocytes was examined.

In addition, 1 unit (unit; U) of lysozyme activity is Micrococcus lysodeik
The amount of lysozyme is such that lysozyme is allowed to act on a suspension of microbial cells as a substrate, and the absorbance at a wavelength of 450 mμ is reduced by 0.001 per minute when measured at pH 6.24 and a temperature of 25 ° C. The results of the activity test are shown in Table 1.

The cell differentiation inducer of the present invention is useful as, for example, a carcinostatic agent, an antimuscular dystrophy agent and the like. When administered as a carcinostatic agent to cancer patients, it is administered by various routes such as oral administration, rectal administration, systemic administration such as intravenous or intramuscular administration, and local administration or transdermal administration to cancer tissue. You can be a patient. In the case of intravenous administration, the dose is usually 1 adult
About 1 to 100 mg / kg per day, usually about 5 to 500 mg per day for adults when oral administration is 1 to 3 per day
It may be administered once or every 2 to 5 days, but it should be appropriately increased or decreased depending on the type and progression of cancer, the age of patients, symptoms, treatment purpose, administration route and the like. The acute toxicity of the cell differentiation inducer of the present invention is LD ₅₀ > 100 mg / kg when intraperitoneally administered to mice.

The cell differentiation inducer of the present invention is preferably used as a cell differentiation inducer composition together with other formulation components generally used in pharmacy. Examples of the composition include injections, drops, capsules, tablets, granules, fine granules, syrups,
Examples thereof include eye drops, ear drops, percutaneous absorption agents, enteric coated capsules, suppositories and the like. The formulation ingredients are lactose,
Excipients such as crystalline cellulose, disintegrants such as carboxymethylcellulose, binders such as hydroxypropylcellulose, lubricants such as magnesium stearate, coating agents such as hydroxypropylmethylcellulose, bases such as polyethylene glycol, physiological saline. And the like, pH adjusting agents such as inorganic acids, isotonic agents such as sodium chloride, or stabilizers.

Formulation examples are specifically shown below.

Formulation Example 1 (Injection / Drip) Add 5 g of powdered glucose to contain cotylenin C 10 mg, aseptically distribute to vials, seal, and seal with an inert gas such as nitrogen and helium, and store in a cool dark place. . Before use, dissolve in hydrous ethanol and add 0.85% physiological saline 10
0 ml is added to make an intravenous injection solution, and 10 to 100 ml is administered by intravenous injection or drip infusion daily depending on the condition.

Formulation Example 2 (Injection / Drip) Cotylenin C 2 mg is used to prepare a mild intravenous injection in the same manner as in Formulation Example 1, and 10 to 100 ml is administered by intravenous injection or drip infusion per day depending on the symptoms. .

Formulation Example 3 (Enteric coated capsule) Take 5 mg of cotylenin C, 2.46 g of lactose and 0.04 g of hydroxypropyl cellulose, mix well, form into granules according to a conventional method, dry this well and sieve it into bottles,
Manufacture granules suitable for heat-sealing packaging. Next, 0.5 g of cellulose acetate phthalate and 0.5 g of hydroxypropylmethyl cellulose phthalate are dissolved to form a coated base material, and the granules are allowed to float and flow, and the base material is coated to form an enteric coated granule. This composition is filled into capsules to produce 100 enteric-coated capsule preparations.

(Effects of the Invention) The cell differentiation inducer provided by the present invention exerts a carcinostatic effect by inducing differentiation into normal cells rather than killing cancer cells when used as a carcinostatic agent, and therefore has few side effects. Useful for treatment.

Claims (3)

[Claims] 1. A cell differentiation inducer having the following structure 2. A cell differentiation inducer composition containing the cell differentiation inducer according to claim 1 as an active ingredient. 3. The cell differentiation inducer according to claim 1, which is used as an anticancer agent.