JPH0680572A - Carcinostatic - Google Patents

Abstract

PURPOSE:To provide a carcinostatic capable of suppressing and preventing carcinogenesis. CONSTITUTION:The objective carcinostatic containing, as active ingredient(s), at least one compound selected from squalene, lanosterol, ergocalciferol, calciferol, 7-dehydrocholesterol, hydrocortisone, dexamethasone, cholic acid and deoxycholic acid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a carcinogen preventive agent for suppressing the occurrence of cancer and preventing carcinogenesis.

[0002]

BACKGROUND OF THE INVENTION The death toll from bladder cancer in Japan is about 1% of the deaths from all malignant tumors, but it has been gradually increasing in recent years. Bladder cancer also includes invasive cancer of high malignancy, but most (70-80)
%) Are superficial cancers. At present, as a rule, bladder conservative therapy, mainly transurethral electroablation, is applied to the treatment of superficial cancers, and the 5-year survival rate is 80 to 90%, which is a good result that exceeds the common sense of malignant tumors in general. Show prognosis. However, a similar cancer recurrence (ectopic recurrence) frequently occurs at another place in the bladder after the operation, which is a great obstacle for the patient to live a social life.

In the conventional development of drugs for treating cancer, those which suppress the growth of cancer cells or those which have the effect of necrosis are the mainstream, but not the treatment of cancer but the suppression of the occurrence of cancer. It is also important. Although some reports have already been made on basic studies of substances showing a carcinogenic promotion-suppressing activity, there is no drug clinically used as a carcinogenic preventive agent.

Therefore, it has been desired to develop a carcinogenesis preventive agent for suppressing the occurrence of cancer and preventing carcinogenesis.

[0005]

Means for Solving the Problems To solve the above problems, the present inventors have conducted extensive studies on the carcinogenicity-preventing effect and found that steroids have a carcinogenic promotion-suppressing activity.

That is, the present invention relates to squalene, lanosterol, ergocalciferol, calciferol,
It is a carcinogenic agent containing at least one compound selected from 7-dehydrocholesterol, hydrocortisone, dexamethasone, cholic acid and deoxycholic acid (hereinafter collectively referred to as the agent of the present invention) as an active ingredient.

The drug of the present invention is represented by the following structural formula:
Commercially available products from Sigma Co., Wako Pure Chemical Industries, Ltd., etc. can be used.

Squalene (Compound 1)

Lanosterol (Compound 2)

Ergocalciferol (Compound 3)

Calciferol (Compound 4)

7-dehydrocholesterol (compound 5)

Hydrocortisone (Compound 6)

Dexamethasone (Compound 7)

Cholic acid (compound 8)

Deoxycholic acid (compound 9)

Next, the fact that the drug of the present invention has a carcinogenic promotion suppressing activity will be described with reference to experimental examples.

Experimental Example Method of Administering Test Sample First, 0.01% BHBN [n-butyl-N] was used as an initiator in male Wistar rats.
-(4-Hydroxybutyl) nitrosamine, Tokyo Kasei Co., Ltd.] An aqueous solution was freely ingested. One week later, it was classified into the following three groups, and the experiment was conducted for 3 weeks as follows.

Group A: Only powdered feed MF [Oriental Yeast Co., Ltd.] was given. Group B: Powdered feed MF containing saccharin sodium [SS, Wako Pure Chemical Industries, Ltd.] at a concentration of 5% as a carcinogenic promoter was given. Group C: The feed MF containing the drug of the present invention and SS was given.

Agglutination test method Rats were sacrificed by ether anesthesia and the bladder was excised.
Excised bladder PBS ^- (135 mM sodium chloride,
2.7 mM potassium chloride, 8.1 mM disodium phosphate dodecahydrate, 1.46 mM potassium phosphate, pH
After washing in 7.4), the bladder was inverted with a pair of tweezers and ligated. 1 ml of PBS ^- was added to the bladder with a syringe to inflate, and 2 ml of EDTA solution (5
mM ethylenediaminetetraacetic acid, 150 mM sodium chloride, pH 7.4) was added, and the mixture was allowed to stand at room temperature for 30 minutes. Then, after removing the bladder epithelial cells with ultrasonic waves, 70 ×
Centrifuge at 1 g for 1 min to remove tissue and resuspend supernatant at 170
Centrifuge for 5 minutes at 0xg. 2m of purified water on this sediment
l was added lysed after a further tonicity such as addition of 0.3M sodium chloride solution 2 ml, was centrifuged for 5 minutes at again 1700 × g, and finally collect sediment cells, PBS ^- with 6
It was adjusted to 9 × 10 ⁶ cells / ml to prepare an epithelial cell suspension.

PBS ^- 20 μ in 10 μl of epithelial cell suspension
l and Con A [Concanavalin A (Concanav
alin A), PBS ^- Medium 3.2 mg / ml, Sigma] 10μl, α-MM [α- methyl mannopyranoside (α-methyl mannopyranosid
e), PBS ^- Medium 6.4 mg / ml, Sigma] 10 [mu]
What added 1 was adjusted. After shaking and stirring these in an incubator at 37 ° C for 30 minutes, 0.5%
After adding 40 μl of Trypan Blue PBS ⁻ solution, the cells were stained and examined under a magnification of 200 ×. At this time, the aggregate of 4 or more cells was regarded as an aggregate, and the number of aggregates per 200 cells was counted. In addition, the aggregation ability suppression rate was calculated with respect to the value of group C with respect to group B. The results are shown in Tables 1 and 2.

Table 1

Table 2

As is clear from the above results, it was confirmed that the group to which the drug of the present invention was administered (group C) had a significant carcinogenic promotion inhibitory activity as compared to the non-administered group (group B). Therefore, the drug of the present invention is considered to be useful as a carcinogenesis preventive agent.

Regarding the toxicity of the drug of the present invention, it is known that the results are shown in Table 3, and it is confirmed that the drug has extremely low toxicity and high safety.

Table 3

Next, the dose and formulation of the drug of the present invention will be described.

The drug of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier.
The dosage form is not particularly limited and may be appropriately selected and used as necessary, and may be tablets, capsules, granules, fine granules,
Examples thereof include oral agents such as powders, parenteral agents such as injections and suppositories.

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight, and degree of disease of the patient, but usually 30 mg to 3 g as the weight of the drug of the present invention in adults.
It seems appropriate to take several doses a day.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used in a conventional manner.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a perfume, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The agents of the present invention can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents. Good.

In order to exert the desired effect as a parenteral agent, it depends on the age, weight and degree of disease of the patient.
The weight of the drug of the present invention is usually 0.1 to 50 per day for adults.
Intravenous injection up to 0 mg, intravenous drip injection, subcutaneous injection, and intramuscular injection seem to be appropriate.

This parenteral preparation is manufactured according to a conventional method and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the present invention will be described in more detail by showing examples of the pharmaceutical preparation of the present invention, but the present invention is not limited thereto.

Example 1 Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Compound 1 10 g Total 100 g According to the above formulation, It was compression molded to obtain tablets of 200 mg each. Each tablet contains 20 mg of Compound 1, and
Take 10 to 25 tablets several times daily.

Example 2 Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound 2 10 g Total 100 g According to the above formulation, a part of and was uniformly mixed, compression molded and crushed, The remaining amounts of and were added and mixed, and the mixture was compression-molded with a tableting machine to obtain 200 mg tablets. 20 mg of Compound 2 is contained in one tablet, and 10 to 25 tablets for adults are to be taken in several divided doses per day.

Example 3 Crystalline Cellulose 79.5 g 10% Hydroxypropyl Cellulose Ethanol Solution 50 g Carboxymethyl Cellulose Calcium 5 g Magnesium Stearate 0.5 g Compound 4 10 g Total 145 g According to the above formulation, and were uniformly mixed, and according to a conventional method. After blending, granulating with an extrusion granulator, drying and crushing, and were mixed and compression-molded with a tableting machine, one tablet of 200 mg was obtained. Each tablet contains 20 mg of Compound 4 and
Take 0 to 25 tablets in several divided doses.

Example 4 Cornstarch 84 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound 5 10 g Total 100 g According to the above formulation, the The granules were obtained by crushing with a crusher and sieving. 1 g of this granule contains 100 mg of Compound 5, and 2 to 5 g of an adult is taken in several divided doses per day.

Example 5 Crystalline Cellulose 86.5 g 10% Hydroxypropyl Cellulose Ethanol Solution 35 g Compound 7 10 g Total 131.5 g According to the above-mentioned prescription, were uniformly mixed and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains 100 m of compound 7
g is included, and 2 to 5 g for an adult is divided into several doses and taken.

Example 6 Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Compound 8 10 g Total 100 g According to the above-mentioned recipe, 1 to were uniformly mixed to obtain 200 mg.
Was filled in a No. 2 capsule. 20 mg of Compound 8 is contained in 1 capsule of this capsule, and 10 to 25 capsules of an adult are taken in several divided doses per day.

Example 7 Distilled water for injection 89.5 g Soybean oil 5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound 9 1 g Total amount 100 g According to the above formula, was dissolved in and and the solution of and was added to emulsify, An injection was obtained.

Claims (1)

[Claims] 1. A carcinogen preventive agent comprising at least one compound selected from squalene, lanosterol, ergocalciferol, calciferol, 7-dehydrocholesterol, hydrocortisone, dexamethasone, cholic acid and deoxycholic acid as an active ingredient.